Biochemistry, Genetics and Molecular Biology › Molecular Biology

Peroxisome Proliferator-Activated Receptors

Works Count: 54083

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This cluster of papers focuses on the Peroxisome Proliferator-Activated Receptors (PPARs), a group of nuclear receptors that play a crucial role in regulating metabolism, inflammation, lipid physiology, and various metabolic diseases such as obesity and diabetes. The cluster explores the diverse biology, mechanisms of action, and therapeutic implications of PPARs, including their involvement in transcriptional regulation and the role of fatty acid-binding proteins.

Keywords

Peroxisome Proliferator-Activated Receptors; PPARs; metabolism; inflammation; lipid; nuclear receptors; obesity; diabetes; fatty acid-binding proteins; transcriptional regulation

The common PPARγ Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes

2000-09-01

David Altshuler , Joel N. Hirschhorn , Mia Klannemark +7 more

Dominant negative mutations in human PPARγ associated with severe insulin resistance, diabetes mellitus and hypertension

1999-12-01

Inês Barroso , Mark Gurnell , Vivion Crowley +7 more

A Pro12Ala substitution in PPARγ2 associated with decreased receptor activity, lower body mass index and improved insulin sensitivity

1998-11-01

Samir S. Deeb , Lluís Fajas , Masami Nemoto +6 more

The peroxisome proliferator-activated receptor-γ is a negative regulator of macrophage activation

1998-01-01

Mercedes Ricote , Andrew C. Li , Timothy M. Willson +2 more

PPAR-γ agonists inhibit production of monocyte inflammatory cytokines

1998-01-01

Chengyu Jiang , Adrian T. Ting , Brian Seed

Roles of PPARs in health and disease

2000-05-01

Sander Kersten , Béatrice Desvergne , Walter Wahli

The PPARα–leukotriene B4 pathway to inflammation control

1996-11-01

Pallavi R. Devchand , H. J. Keller , Jeffrey M. Peters +3 more

PPARγ Is Required for Placental, Cardiac, and Adipose Tissue Development

1999-10-01

Yaacov Barak , Michael C. Nelson , Estelita S. Ong +5 more

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PPARγ Promotes Monocyte/Macrophage Differentiation and Uptake of Oxidized LDL

1998-04-01

Peter Tontonoz , László Nagy , Jacqueline G. Alvarez +2 more

The PPARs: From Orphan Receptors to Drug Discovery

2000-02-01

Timothy M. Willson , Peter J. Brown , Daniel D. Sternbach +1 more

ADVERTISEMENT RETURN TO ISSUEPerspectiveNEXTThe PPARs: From Orphan Receptors to Drug Discovery†Timothy M. Willson, Peter J. Brown, Daniel D. Sternbach, and Brad R. HenkeView Author Information Department of Medicinal Chemistry, Glaxo … ADVERTISEMENT RETURN TO ISSUEPerspectiveNEXTThe PPARs: From Orphan Receptors to Drug Discovery†Timothy M. Willson, Peter J. Brown, Daniel D. Sternbach, and Brad R. HenkeView Author Information Department of Medicinal Chemistry, Glaxo Wellcome Research & Development, Research Triangle Park, North Carolina 27709 Cite this: J. Med. Chem. 2000, 43, 4, 527–550Publication Date (Web):February 24, 2000Publication History Received8 November 1999Published online24 February 2000Published inissue 1 February 2000https://pubs.acs.org/doi/10.1021/jm990554ghttps://doi.org/10.1021/jm990554greview-articleACS PublicationsCopyright © 2000 American Chemical SocietyRequest reuse permissionsArticle Views6740Altmetric-Citations1452LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Agonists,Ligands,Lipids,Receptors,Rodent models Get e-Alerts

Control of the peroxisomal β-oxidation pathway by a novel family of nuclear hormone receptors

1992-03-01

Christine Dreyer , Grigorios Krey , H. J. Keller +3 more

Convergence of 9-cis retinoic acid and peroxisome proliferator signalling pathways through heterodimer formation of their receptors

1992-08-01

Steven A. Kliewer , Kazuhiko Umesono , Daniel J. Noonan +2 more

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Hypolipidemic drugs, polyunsaturated fatty acids, and eicosanoids are ligands for peroxisome proliferator-activated receptors α and δ

1997-04-29

Barry M. Forman , Jasmine Chen , Ronald M. Evans

Fatty acids (FAs) and their derivatives are essential cellular metabolites whose concentrations must be closely regulated. This implies that regulatory circuits exist which can sense changes in FA levels. Indeed, … Fatty acids (FAs) and their derivatives are essential cellular metabolites whose concentrations must be closely regulated. This implies that regulatory circuits exist which can sense changes in FA levels. Indeed, the peroxisome proliferator-activated receptor alpha (PPARalpha) regulates lipid homeostasis and is transcriptionally activated by a variety of lipid-like compounds. It remains unclear as to how these structurally diverse compounds can activate a single receptor. We have developed a novel conformation-based assay that screens activators for their ability to bind to PPARalpha/delta and induce DNA binding. We show here that specific FAs, eicosanoids, and hypolipidemic drugs are ligands for PPARalpha or PPARdelta. Because altered FA levels are associated with obesity, atherosclerosis, hypertension, and diabetes, PPARs may serve as molecular sensors that are central to the development and treatment of these metabolic disorders.

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Fatty acid-binding proteins: role in metabolic diseases and potential as drug targets

2008-05-30

Masato Furuhashi , Gökhan S. Hotamışlıgil

Stimulation of adipogenesis in fibroblasts by PPARγ2, a lipid-activated transcription factor

1994-12-01

Peter Tontonoz , Erding Hu , Bruce M. Spiegelman

15-Deoxy-Δ12,14-Prostaglandin J2 is a ligand for the adipocyte determination factor PPARγ

1995-12-01

Barry M. Forman , Peter Tontonoz , Jasmine Chen +3 more

Peroxisome-Proliferator-Activated Receptor δ Activates Fat Metabolism to Prevent Obesity

2003-04-01

Yong‐Xu Wang , Chih‐Hao Lee , Sambath Tiep +4 more

Peroxisome Proliferator-Activated Receptors: Nuclear Control of Metabolism*

1999-10-01

Béatrice Desvergne , Walter Wahli

I. Introduction II. Molecular Aspects A. PPAR isotypes: identity, genomic organization and chromosomal localization B. DNA binding properties C. PPAR ligand-binding properties D. Alternative pathways for PPAR activation E. PPAR-mediated … I. Introduction II. Molecular Aspects A. PPAR isotypes: identity, genomic organization and chromosomal localization B. DNA binding properties C. PPAR ligand-binding properties D. Alternative pathways for PPAR activation E. PPAR-mediated transactivation properties III. Physiological Aspects A. Differential expression of PPAR mRNAs B. PPAR target genes and functions in fatty acid metabolism C. PPARs and control of inflammatory responses D. PPARs and atherosclerosis E. PPARs and the development of the fetal epidermal permeability barrier F. PPARs, carcinogenesis, and control of the cell cycle IV. Conclusions

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The Many Faces of PPARγ

2005-12-01

Michael Lehrke , Mitchell A. Lazar

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Combination of high-fat diet-fed and low-dose streptozotocin-treated rat: A model for type 2 diabetes and pharmacological screening

2005-06-25

K. K. Srinivasan , Bhoomi Viswanad , Lydia Asrat +2 more

An Antidiabetic Thiazolidinedione Is a High Affinity Ligand for Peroxisome Proliferator-activated Receptor γ (PPARγ)

1995-06-01

Jürgen M. Lehmann , Linda B. Moore , Tracey Smith-Oliver +3 more

A SUMOylation-dependent pathway mediates transrepression of inflammatory response genes by PPAR-γ

2005-08-28

Gabriel Pascual , Amy L. Fong , Sumito Ogawa +7 more

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Differential expression of peroxisome proliferator-activated receptors (PPARs): tissue distribution of PPAR-alpha, -beta, and -gamma in the adult rat.

1996-01-01

Olivier Braissant , Fabienne Foufelle , Christian Scotto +2 more

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily that can be activated by various xenobiotics and natural fatty acids. These transcription factors primarily regulate genes involved … Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily that can be activated by various xenobiotics and natural fatty acids. These transcription factors primarily regulate genes involved in lipid metabolism and also play a role in adipocyte differentiation. We present the expression patterns of the PPAR subtypes in the adult rat, determined by in situ hybridization using specific probes for PPAR-alpha, -beta and -gamma, and by immunohistochemistry using a polyclonal antibody that recognizes the three rat PPAR subtypes. In numerous cell types from either ectodermal, mesodermal, or endodermal origin, PPARs are coexpressed, with relative levels varying between them from one cell type to the other. PPAR-alpha is highly expressed in hepatocytes, cardiomyocytes, enterocytes, and the proximal tubule cells of kidney. PPAR-beta is expressed ubiquitously and often at higher levels than PPAR-alpha and -gamma. PPAR-gamma is expressed predominantly in adipose tissue and the immune system. Our results suggest new potential directions to investigate the functions of the different PPAR subtypes.

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A prostaglandin J2 metabolite binds peroxisome proliferator-activated receptor γ and promotes adipocyte differentiation

1995-12-01

Steven A. Kliewer , James M. Lenhard , Timothy M. Willson +3 more

Mechanism of Action of Fibrates on Lipid and Lipoprotein Metabolism

1998-11-10

Bart Staels , Jean Dallongeville , Johan Auwerx +3 more

Abstract —Treatment with fibrates, a widely used class of lipid-modifying agents, results in a substantial decrease in plasma triglycerides and is usually associated with a moderate decrease in LDL cholesterol … Abstract —Treatment with fibrates, a widely used class of lipid-modifying agents, results in a substantial decrease in plasma triglycerides and is usually associated with a moderate decrease in LDL cholesterol and an increase in HDL cholesterol concentrations. Recent investigations indicate that the effects of fibrates are mediated, at least in part, through alterations in transcription of genes encoding for proteins that control lipoprotein metabolism. Fibrates activate specific transcription factors belonging to the nuclear hormone receptor superfamily, termed peroxisome proliferator-activated receptors (PPARs). The PPAR-α form mediates fibrate action on HDL cholesterol levels via transcriptional induction of synthesis of the major HDL apolipoproteins, apoA-I and apoA-II. Fibrates lower hepatic apoC-III production and increase lipoprotein lipase—mediated lipolysis via PPAR. Fibrates stimulate cellular fatty acid uptake, conversion to acyl-CoA derivatives, and catabolism by the β-oxidation pathways, which, combined with a reduction in fatty acid and triglyceride synthesis, results in a decrease in VLDL production. In summary, both enhanced catabolism of triglyceride-rich particles and reduced secretion of VLDL underlie the hypotriglyceridemic effect of fibrates, whereas their effect on HDL metabolism is associated with changes in HDL apolipoprotein expression.

Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators

1990-10-01

Isabelle Issemann , Stephen Green

Molecular mechanism of PPARα action and its impact on lipid metabolism, inflammation and fibrosis in non-alcoholic fatty liver disease

2014-11-01

Michał Pawlak , Philippe Lefèbvre , Bart Staels

Peroxisome proliferator-activated receptor α (PPARα) is a ligand-activated transcription factor belonging, together with PPARγ and PPARβ/δ, to the NR1C nuclear receptor subfamily. Many PPARα target genes are involved in fatty … Peroxisome proliferator-activated receptor α (PPARα) is a ligand-activated transcription factor belonging, together with PPARγ and PPARβ/δ, to the NR1C nuclear receptor subfamily. Many PPARα target genes are involved in fatty acid metabolism in tissues with high oxidative rates such as muscle, heart and liver. PPARα activation, in combination with PPARβ/δ agonism, improves steatosis, inflammation and fibrosis in pre-clinical models of non-alcoholic fatty liver disease, identifying a new potential therapeutic area. In this review, we discuss the transcriptional activation and repression mechanisms by PPARα, the spectrum of target genes and chromatin-binding maps from recent genome-wide studies, paying particular attention to PPARα-regulation of hepatic fatty acid and plasma lipoprotein metabolism during nutritional transition, and of the inflammatory response. The role of PPARα, together with other PPARs, in non-alcoholic steatohepatitis will be discussed in light of available pre-clinical and clinical data.

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PPARγ signaling and metabolism: the good, the bad and the future

2013-05-01

Maryam Ahmadian , Jae Myoung Suh , Nasun Hah +4 more

Oxidized LDL Regulates Macrophage Gene Expression through Ligand Activation of PPARγ

1998-04-01

László Nagy , Peter Tontonoz , Jacqueline G. Alvarez +2 more

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PPARγ Is Required for the Differentiation of Adipose Tissue In Vivo and In Vitro

1999-10-01

Evan D. Rosen , Pasha Sarraf , Amy E. Troy +5 more

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Fat and Beyond: The Diverse Biology of PPARγ

2008-03-20

Peter Tontonoz , Bruce M. Spiegelman

The nuclear receptor PPARgamma is a ligand-activated transcription factor that plays an important role in the control of gene expression linked to a variety of physiological processes. PPARgamma was initially … The nuclear receptor PPARgamma is a ligand-activated transcription factor that plays an important role in the control of gene expression linked to a variety of physiological processes. PPARgamma was initially characterized as the master regulator for the development of adipose cells. Ligands for PPARgamma include naturally occurring fatty acids and the thiazolidinedione (TZD) class of antidiabetic drugs. Activation of PPARgamma improves insulin sensitivity in rodents and humans through a combination of metabolic actions, including partitioning of lipid stores and the regulation of metabolic and inflammatory mediators termed adipokines. PPARgamma signaling has also been implicated in the control of cell proliferation, atherosclerosis, macrophage function, and immunity. Here, we review recent advances in our understanding of the diverse biological actions of PPARgamma with an eye toward the expanding therapeutic potential of PPARgamma agonist drugs.

Peroxisome proliferator–activated receptor α mediates the adaptive response to fasting

1999-06-01

Sander Kersten , Josiane Seydoux , Jeffrey M. Peters +3 more

Prolonged deprivation of food induces dramatic changes in mammalian metabolism, including the release of large amounts of fatty acids from the adipose tissue, followed by their oxidation in the liver. … Prolonged deprivation of food induces dramatic changes in mammalian metabolism, including the release of large amounts of fatty acids from the adipose tissue, followed by their oxidation in the liver. The nuclear receptor known as peroxisome proliferator–activated receptor α (PPARα) was found to play a role in regulating mitochondrial and peroxisomal fatty acid oxidation, suggesting that PPARα may be involved in the transcriptional response to fasting. To investigate this possibility, PPARα-null mice were subjected to a high fat diet or to fasting, and their responses were compared with those of wild-type mice. PPARα-null mice chronically fed a high fat diet showed a massive accumulation of lipid in their livers. A similar phenotype was noted in PPARα-null mice fasted for 24 hours, who also displayed severe hypoglycemia, hypoketonemia, hypothermia, and elevated plasma free fatty acid levels, indicating a dramatic inhibition of fatty acid uptake and oxidation. It is shown that to accommodate the increased requirement for hepatic fatty acid oxidation, PPARα mRNA is induced during fasting in wild-type mice. The data indicate that PPARα plays a pivotal role in the management of energy stores during fasting. By modulating gene expression, PPARα stimulates hepatic fatty acid oxidation to supply substrates that can be metabolized by other tissues.

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Differential expression and activation of a family of murine peroxisome proliferator-activated receptors.

1994-07-19

Steven A. Kliewer , Barry M. Forman , Bruce Blumberg +5 more

To gain insight into the function of peroxisome proliferator-activated receptor (PPAR) isoforms in mammals, we have cloned and characterized two PPAR alpha-related cDNAs (designated PPAR gamma and -delta, respectively) from … To gain insight into the function of peroxisome proliferator-activated receptor (PPAR) isoforms in mammals, we have cloned and characterized two PPAR alpha-related cDNAs (designated PPAR gamma and -delta, respectively) from mouse. The three PPAR isoforms display widely divergent patterns of expression during embryogenesis and in the adult. Surprisingly, PPAR gamma and -delta are not activated by pirinixic acid (Wy 14,643), a potent peroxisome proliferator and activator of PPAR alpha. However, PPAR gamma and -delta are activated by the structurally distinct peroxisome proliferator LY-171883 and linoleic acid, respectively, indicating that each of the isoforms can act as a regulated activator of transcription. These data suggest that tissue-specific responsiveness to peroxisome proliferators, including certain fatty acids, is in part a consequence of differential expression of multiple, pharmacologically distinct PPAR isoforms.

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The Mechanisms of Action of PPARs

2002-02-01

Joel P. Berger , David E. Moller

▪ Abstract The peroxisome proliferator-activated receptors (PPARs) are a group of three nuclear receptor isoforms, PPARγ, PPARα, and PPARδ, encoded by different genes. PPARs are ligand-regulated transcription factors that control … ▪ Abstract The peroxisome proliferator-activated receptors (PPARs) are a group of three nuclear receptor isoforms, PPARγ, PPARα, and PPARδ, encoded by different genes. PPARs are ligand-regulated transcription factors that control gene expression by binding to specific response elements (PPREs) within promoters. PPARs bind as heterodimers with a retinoid X receptor and, upon binding agonist, interact with cofactors such that the rate of transcription initiation is increased. The PPARs play a critical physiological role as lipid sensors and regulators of lipid metabolism. Fatty acids and eicosanoids have been identified as natural ligands for the PPARs. More potent synthetic PPAR ligands, including the fibrates and thiazolidinediones, have proven effective in the treatment of dyslipidemia and diabetes. Use of such ligands has allowed researchers to unveil many potential roles for the PPARs in pathological states including atherosclerosis, inflammation, cancer, infertility, and demyelination. Here, we present the current state of knowledge regarding the molecular mechanisms of PPAR action and the involvement of the PPARs in the etiology and treatment of several chronic diseases.

Ligand binding and co-activator assembly of the peroxisome proliferator-activated receptor-γ

1998-09-01

Robert T. Nolte , G. Bruce Wisely , Stefan Westin +7 more

Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial

2006-09-01

Hertzel C. Gerstein , Salim Yusuf , Jackie Bosch +7 more

Targeted Disruption of the α Isoform of the Peroxisome Proliferator-Activated Receptor Gene in Mice Results in Abolishment of the Pleiotropic Effects of Peroxisome Proliferators

1995-06-01

Susanna S.T. Lee , Thierry Pineau , John Drago +6 more

To gain insight into the function of peroxisome proliferator-activated receptor (PPAR) isoforms in rodents, we disrupted the ligand-binding domain of the alpha isoform of mouse PPAR (mPPAR alpha) by homologous … To gain insight into the function of peroxisome proliferator-activated receptor (PPAR) isoforms in rodents, we disrupted the ligand-binding domain of the alpha isoform of mouse PPAR (mPPAR alpha) by homologous recombination. Mice homozygous for the mutation lack expression of mPPAR alpha protein and yet are viable and fertile and exhibit no detectable gross phenotypic defects. Remarkably, these animals do not display the peroxisome proliferator pleiotropic response when challenged with the classical peroxisome proliferators, clofibrate and Wy-14,643. Following exposure to these chemicals, hepatomegaly, peroxisome proliferation, and transcriptional-activation of target genes were not observed. These results clearly demonstrate that mPPAR alpha is the major isoform required for mediating the pleiotropic response resulting from the actions of peroxisome proliferators. mPPAR alpha-deficient animals should prove useful to further investigate the role of this receptor in hepatocarcinogenesis, fatty acid metabolism, and cell cycle regulation.

PPAR-gamma: adipogenic regulator and thiazolidinedione receptor.

1998-04-01

Bruce M. Spiegelman

The past several years have seen an explosive increase in our understanding of the transcriptional basis of adipose cell differentiation. In particular, a key role has been illustrated for PPAR-gamma, … The past several years have seen an explosive increase in our understanding of the transcriptional basis of adipose cell differentiation. In particular, a key role has been illustrated for PPAR-gamma, a member of the nuclear hormone receptor superfamily. PPAR-gamma has also been recently identified as the major functional receptor for the thiazolidinedione class of insulin-sensitizing drugs. This review examines the evidence that has implicated this transcription factor in the processes of adipogenesis and systemic insulin action. In addition, several models are discussed that may explain how a single protein can be involved in these related but distinct physiological actions. I also point out several important areas where our knowledge is incomplete and more research is needed. Finally, I discuss how advances in our understanding of nuclear receptor function, particularly the docking of cofactors in a ligand-dependent fashion, should lead to improved drugs that utilize the PPAR-gamma system for the treatment of insulin resistance.

Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes

2007-05-22

Steven E. Nissen , Kathy Wolski

Rosiglitazone is widely used to treat patients with type 2 diabetes mellitus, but its effect on cardiovascular morbidity and mortality has not been determined.We conducted searches of the published literature, … Rosiglitazone is widely used to treat patients with type 2 diabetes mellitus, but its effect on cardiovascular morbidity and mortality has not been determined.We conducted searches of the published literature, the Web site of the Food and Drug Administration, and a clinical-trials registry maintained by the drug manufacturer (GlaxoSmithKline). Criteria for inclusion in our meta-analysis included a study duration of more than 24 weeks, the use of a randomized control group not receiving rosiglitazone, and the availability of outcome data for myocardial infarction and death from cardiovascular causes. Of 116 potentially relevant studies, 42 trials met the inclusion criteria. We tabulated all occurrences of myocardial infarction and death from cardiovascular causes.Data were combined by means of a fixed-effects model. In the 42 trials, the mean age of the subjects was approximately 56 years, and the mean baseline glycated hemoglobin level was approximately 8.2%. In the rosiglitazone group, as compared with the control group, the odds ratio for myocardial infarction was 1.43 (95% confidence interval [CI], 1.03 to 1.98; P=0.03), and the odds ratio for death from cardiovascular causes was 1.64 (95% CI, 0.98 to 2.74; P=0.06).Rosiglitazone was associated with a significant increase in the risk of myocardial infarction and with an increase in the risk of death from cardiovascular causes that had borderline significance. Our study was limited by a lack of access to original source data, which would have enabled time-to-event analysis. Despite these limitations, patients and providers should consider the potential for serious adverse cardiovascular effects of treatment with rosiglitazone for type 2 diabetes.

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Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors α and γ

1997-04-29

Steven A. Kliewer , Scott S. Sundseth , Stacey A. Jones +7 more

Peroxisome proliferator-activated receptors (PPARs) α and γ are key regulators of lipid homeostasis and are activated by a structurally diverse group of compounds including fatty acids, eicosanoids, and hypolipidemic drugs … Peroxisome proliferator-activated receptors (PPARs) α and γ are key regulators of lipid homeostasis and are activated by a structurally diverse group of compounds including fatty acids, eicosanoids, and hypolipidemic drugs such as fibrates and thiazolidinediones. While thiazolidinediones and 15-deoxy-Δ 12,14 -prostaglandin J 2 have been shown to bind to PPARγ, it has remained unclear whether other activators mediate their effects through direct interactions with the PPARs or via indirect mechanisms. Here, we describe a novel fibrate, designated GW2331, that is a high-affinity ligand for both PPARα and PPARγ. Using GW2331 as a radioligand in competition binding assays, we show that certain mono- and polyunsaturated fatty acids bind directly to PPARα and PPARγ at physiological concentrations, and that the eicosanoids 8(S)-hydroxyeicosatetraenoic acid and 15-deoxy-Δ 12,14 -prostaglandin J 2 can function as subtype-selective ligands for PPARα and PPARγ, respectively. These data provide evidence that PPARs serve as physiological sensors of lipid levels and suggest a molecular mechanism whereby dietary fatty acids can modulate lipid homeostasis.

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Role of the peroxisome proliferator-activated receptor (PPAR) in mediating the effects of fibrates and fatty acids on gene expression

1996-05-01

Kristina Schoonjans , Bart Staels , Johan Auwerx

The three types of peroxisome proliferator-activated receptors (PPAR), termed alpha, delta (or beta), and gamma, belong to the nuclear receptor superfamily. Although peroxisome proliferators, including fibrates and fatty acids, activate … The three types of peroxisome proliferator-activated receptors (PPAR), termed alpha, delta (or beta), and gamma, belong to the nuclear receptor superfamily. Although peroxisome proliferators, including fibrates and fatty acids, activate the transcriptional activity of these receptors, only prostaglandin J2 derivatives have been identified as natural ligands of the PPAR gamma subtype that also binds thiazolidinedione antidiabetic agents with high affinity. PPARs heterodimerize with retinoic X receptor (RXR) and alter the transcription of target genes after binding to response elements or PPREs, consisting of a direct repeat of the nuclear receptor hexameric DNA recognition motif (PuGGTCA) spaced by 1 nucleotide (DR-1). Upon activation by fatty acids (FAs) and drugs that affect lipid metabolism, PPARs control the expression of genes implicated in intra- and extracellular lipid metabolism, most notably those involved in peroxisomal beta-oxidation. PPARs partially mediate the inductive effects of fibrates and fatty acids on high density lipoprotein (HDL) cholesterol levels by regulating the transcription of the major HDL apolipoproteins, apoA-I and apoA-II. The hypotriglyceridemic action of fibrates and certain fatty acids also involves PPAR and is constituted of: 1) increased hydrolysis of plasma triglycerides due to induction of LPL and reduction of apoC-III expression; 2) stimulation of cellular fatty acid uptake and conversion to acyl-CoA derivatives due to increased expression of genes for fatty acid transport protein and acyl-CoA synthetase; 3) increased peroxisomal and mitochondrial beta-oxidation; and 4) decreased synthesis of fatty acids and triglycerides and decreased production of very low density lipoprotein (VLDL). Hence, both enhanced catabolism of triglyceride-rich particles and reduced secretion of VLDL particles contribute to the hypolipidemic effect of fibrates and fatty acids. Finally, PPARs appear to be involved in differentiation processes because activation of PPAR gamma 2 triggers adipocyte differentiation and stimulates expression of several genes critical to adipogenesis. It is suggested that PPARs are key messengers responsible for the translation of nutritional and pharmacological stimuli into changes in gene expression and differentiation pathways.

PPARγ Mediates High-Fat Diet–Induced Adipocyte Hypertrophy and Insulin Resistance

1999-10-01

Naoto Kubota , Yasuo Terauchi , Hiroshi Miki +7 more

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PPARs and the complex journey to obesity

2004-03-31

Ronald M. Evans , Grant D. Barish , Yong-Xu Wang

mPPAR gamma 2: tissue-specific regulator of an adipocyte enhancer.

1994-05-15

Peter Tontonoz , E Hu , Reed A. Graves +2 more

Previously, we have isolated and characterized an enhancer from the 5'-flanking region of the adipocyte P2 (aP2) gene that directs high-level adipocyte-specific gene expression in both cultured cells and transgenic … Previously, we have isolated and characterized an enhancer from the 5'-flanking region of the adipocyte P2 (aP2) gene that directs high-level adipocyte-specific gene expression in both cultured cells and transgenic mice. The key regulator of this enhancer is a cell type-restricted nuclear factor termed ARF6. Target sequences for ARF6 in the aP2 enhancer exhibit homology to a direct repeat of hormone response elements (HREs) spaced by one nucleotide; this motif (DR-1) has been demonstrated previously to be the preferred binding site for heterodimers of the retinoid X receptor (RXR) and the peroxisome proliferator-activated receptor (PPAR). We have cloned a novel member of the peroxisome proliferator-activated receptor family designated mPPAR gamma 2, and we demonstrate that a heterodimeric complex of mPPAR gamma 2 and RXR alpha constitute a functional ARF6 complex. Expression of mPPAR gamma 2 is induced very early during the differentiation of several cultured adipocyte cell lines and is strikingly adipose-specific in vivo. mPPAR gamma 2 and RXR alpha form heterodimers on ARF6-binding sites in vitro, and antiserum to RXR alpha specifically inhibits ARF6 activity in adipocyte nuclear extracts. Moreover, forced expression of mPPAR gamma 2 and RXR alpha activates the adipocyte-specific aP2 enhancer in cultured fibroblasts, and this activation is potentiated by peroxisome proliferators, fatty acids, and 9-cis retinoic acid. These results identify mPPAR gamma 2 as the first adipocyte-specific transcription factor and suggest mechanisms whereby fatty acids, peroxisome proliferators, 9-cis retinoic acid, and other lipids may regulate adipocyte gene expression and differentiation.

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C/EBPα induces adipogenesis through PPARγ: a unified pathway

2002-01-01

Evan D. Rosen , Chung-Hsin Hsu , Xinzhong Wang +4 more

PPARγ and C/EBPα are critical transcription factors in adipogenesis, but the precise role of these proteins has been difficult to ascertain because they positively regulate each other's expression. Questions remain … PPARγ and C/EBPα are critical transcription factors in adipogenesis, but the precise role of these proteins has been difficult to ascertain because they positively regulate each other's expression. Questions remain about whether these factors operate independently in separate, parallel pathways of differentiation, or whether a single pathway exists. PPARγ can promote adipogenesis in C/EBPα-deficient cells, but the converse has not been tested. We have created an immortalized line of fibroblasts lacking PPARγ, which we use to show that C/EBPα has no ability to promote adipogenesis in the absence of PPARγ. These results indicate that C/EBPα and PPARγ participate in a single pathway of fat cell development with PPARγ being the proximal effector of adipogenesis.

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Thematic review series: The Pathogenesis of Atherosclerosis. Effects of infection and inflammation on lipid and lipoprotein metabolism mechanisms and consequences to the host

2004-06-08

Weerapan Khovidhunkit , Min-Sun Kim , Riaz A. Memon +4 more

Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults--The Evidence Report. National Institutes of Health.

1998-09-01

Anna Meiliana , Andi Wijaya

BACKGROUND: Obesity is a growing threat to global health by virtue of its association with insulin resistance, inflammation, hypertension, and dyslipidemia, collectively known as the metabolic syndrome (MetS). The nuclear … BACKGROUND: Obesity is a growing threat to global health by virtue of its association with insulin resistance, inflammation, hypertension, and dyslipidemia, collectively known as the metabolic syndrome (MetS). The nuclear receptors PPARα and PPARγ are therapeutic targets for hypertriglyceridemia and insulin resistance, respectively, and drugs that modulate these receptors are currently in clinical use. More recent work on the PPARδ has uncovered a dual benefit for both hypertriglyceridemia and insulin resistance, highlighting the broad potential of PPARs in the treatment of metabolic disease. CONTENT: We have learned much about PPARs, the metabolic fat sensors, and the molecular pathways they regulate. Through their distinct tissue distribution and specific target gene activation, the three PPARs together control diverse aspects of fatty acid metabolism, energy balance, insulin sensitivity glucose homeostasis, inflammation, hypertension and atherosclerosis. These studies have advanced our understanding of the etiology for the MetS. Mechanisms revealed by these studies highlight the importance of emerging concepts, such as the endocrine function of adipose tissue, tissue-tissue cross-talk and lipotoxicity, in the pathogenesis of type 2 diabetes mellitus and CVD. SUMMARY: The elucidation of key regulators of energy balance and insulin signaling have revolutionized our understanding of fat and sugar metabolism and their intimate link. The three ‘lipidsensing’ (PPARα, PPARγ and PPARδ) exemplify this connection, regulating diverse aspects of lipid and glucose homeostasis, and serving as bonafide therapeutic targets. KEYWORDS: Peroxisome Proliferator, Activated Receptor, Metabolic Syndrome

Peroxisome proliferator-activated receptor a target genes

2004-02-01

Stéphane Mandard , M. M�ller , Sander Kersten

Thiazolidinediones

2004-09-08

Hannele Yki‐Järvinen

Despite a large need for new hypoglycemic therapies, given the epidemic of type 2 diabetes, very few agents have been introduced during the past 20 years. The thiazolidinediones represent a … Despite a large need for new hypoglycemic therapies, given the epidemic of type 2 diabetes, very few agents have been introduced during the past 20 years. The thiazolidinediones represent a potentially important new group of drugs with a mechanism of action differing from and perhaps complementary to that of existing therapies. This article discusses present data on mechanisms, indications, and limitations of thiazolidinedione therapy.

Peroxisome Proliferator-Activated Receptors: Nuclear Control of Metabolism

1999-10-01

Béatrice Desvergne

Novel gene regulatory networks identified in response to nitro-conjugated linoleic acid in human endothelial cells

2025-09-30

Yanbo Fan , Haocheng Lu

A distinct transcriptome regulated by NO2-CLA was revealed in primary human coronary artery endothelial cells (HCAECs) through RNA sequencing. A distinct transcriptome regulated by NO2-CLA was revealed in primary human coronary artery endothelial cells (HCAECs) through RNA sequencing.

Novel gene regulatory networks identified in response to nitro-conjugated linoleic acid in human endothelial cells

2025-09-30

Yanbo Fan , Haocheng Lu

Mammalian fatty acid synthase: a commonly used viral host dependency factor and a putative target for host-targeted broad-spectrum antiviral therapeutic development

2025-06-25

Paola N. Loperena González , Krithika P. Karthigeyan , Jacqueline Corry +4 more | mBio

ABSTRACT Viruses regulate host processes to create cellular environments favorable to viral replication. At least 27 viruses that infect humans require host fatty acid synthase (FASN)-dependent de novo fatty acid … ABSTRACT Viruses regulate host processes to create cellular environments favorable to viral replication. At least 27 viruses that infect humans require host fatty acid synthase (FASN)-dependent de novo fatty acid biosynthesis, including viruses from the Coronaviridae , Flaviviridae , Herpesviridae, Picornaviridae, Retroviridae, and Togaviridae families. How could FASN activity and subsequent de novo fatty acid production impact viral replication? FASN activity produces the fatty acid palmitate, which can be further metabolized into fatty acids that are used to form lipid droplets that can be used during viral assembly and budding, for beta-oxidation to generate ATP, and to create fatty acyl groups used for post-translational protein modification to change the subcellular localization of viral or host proteins. In this minireview, we outline the function of FASN, review the mechanisms linking virus replication and fatty acid biosynthesis, and consider the potential of FASN as a target for broad-spectrum antiviral drug development.

PEX14 condensates recruit receptor and cargo pairs for peroxisomal protein import

2025-06-24

Jianguo Wu , Shenjin Lv , Peng Xu +2 more | Nature Structural & Molecular Biology

Overview of genetic mutations causing adrenoleukodystrophy: A case-series study

2025-06-24

Mohadeseh Fathi , Sheyda Khalilian , Arezou Sayad +4 more | Molecular Genetics and Metabolism Reports

Status epilepticus as clinical manifestation of adrenomyeloneuropathy: a rare association

2025-06-22

Sandra Perillo , Roberto Allocca , Francesco Barbato +4 more | Deleted Journal

Abstract Adrenomyeloneuropathy (AMN) is a form of the X-linked adrenoleukodystrophy (ALD), a rare peroxisomal beta-oxidation disorder causing the accumulation of very long-chain fatty acids (VLCFAs) in adrenal cortex and central … Abstract Adrenomyeloneuropathy (AMN) is a form of the X-linked adrenoleukodystrophy (ALD), a rare peroxisomal beta-oxidation disorder causing the accumulation of very long-chain fatty acids (VLCFAs) in adrenal cortex and central and peripheral nervous system. We present the case of a 48-year-old man with genetically confirmed AMN, who presented to the Emergency Department with convulsive status epilepticus. The brain MRI showed extensive leukoencephalopathy and demyelination involving bilateral subcortical and deep white matter, corticospinal tracts, corpus callosum and the pons. Correction of laboratory abnormalities and therapy with intravenous levetiracetam, oral phenytoin and perampanel led to significant clinical improvement and resolution of the seizures. Convulsive status epilepticus may be a clinical manifestation of X-linked AMN.

Clinical Variation and Neuroimaging Patterns in Monozygotic Twins With Arrested X-Linked Adrenoleukodystrophy: A Case Report

2025-06-21

Trevor A Leon , Steve Nelson , Alex Gilman +2 more | Cureus

Nitroglycerin

2025-06-21

| Reactions Weekly

In silico identification of PPARγ agonists from diffractaic acid analogs in prostate cancer: a comprehensive computational approach

2025-06-20

Miah Roney , Md. Nazim Uddin , Azmat Ali Khan +3 more | 3 Biotech

Response to Comment on: Hard-flaccid syndrome: a report of two case

2025-06-20

Karl H. Pang , Yan Zhang | International Journal of Impotence Research

Peroxisome dynamics and inter-organelle interactions in neuronal health and disease

2025-06-20

Ruth E. Carmichael | Frontiers in Molecular Neuroscience

Peroxisomes are essential organelles, present in all nucleated cells, with key roles in lipid and redox homeostasis. They are important for maintaining healthy cell function, with defects in peroxisome biogenesis … Peroxisomes are essential organelles, present in all nucleated cells, with key roles in lipid and redox homeostasis. They are important for maintaining healthy cell function, with defects in peroxisome biogenesis and/or metabolism leading to disease. Notably, patients with peroxisomal diseases exhibit predominantly neurological phenotypes, and peroxisomes are observed to be altered in a range of neurodegenerative conditions, highlighting the crucial roles they play in the brain. While most studies so far have focused on the contribution of peroxisomal metabolism, it is becoming apparent that many different aspects of peroxisome biology are necessary for healthy neural function. Peroxisomes are highly dynamic, responding to cellular needs with changes in number, shape and distribution. Furthermore, they do not act in isolation but instead interact and cooperate with a range of organelles to carry out their roles. This review summarizes our current knowledge on the importance of peroxisome dynamics and inter-organelle interactions in neuronal function and dysfunction. It considers their impact on neuronal physiology, and discusses the evidence that defects in these processes are associated with neurological pathophysiology and may thus represent a novel therapeutic target for treating diseases affecting the nervous system. Finally, the review outlines the current knowledge gaps relating to the mechanisms by which peroxisome dynamics and inter-organelle interactions influence neuronal (dys)function, proposing potential new research directions to address these and further our understanding of the multi-faceted roles peroxisomes play in brain health and disease.

The Role of 13-Hydroxyoctadecadienoic Acid, 15-Lipoxygenase, and Peroxisome Proliferator-Activated Receptor Alpha Gene Polymorphism (rs1800206) in Acute Coronary Syndrome: Pathophysiological Insights and Biomarker Relevance

2025-06-20

Abdullah Abdulsattar Raeef , Hassan H. Al-Saeed , Sami Mekhlif Mishlish | Baghdad Journal of Biochemistry and Applied Biological Sciences

Acute Coronary Syndrome (ACS) represents a spectrum of life-threatening cardiovascular conditions characterized by sudden myocardial ischemia. This review synthesizes current knowledge on the pathophysiological roles of 13-hydroxyoctadecadienoic acid (13-HODE), 15-lipoxygenase … Acute Coronary Syndrome (ACS) represents a spectrum of life-threatening cardiovascular conditions characterized by sudden myocardial ischemia. This review synthesizes current knowledge on the pathophysiological roles of 13-hydroxyoctadecadienoic acid (13-HODE), 15-lipoxygenase (15-LOX), and peroxisome proliferator-activated receptor alpha (PPAR-α) in ACS development, with particular emphasis on the PPAR-α rs1800206 (Leu162Val) polymorphism. Emerging evidence highlights the dual role of 13-HODE as both a pro-inflammatory mediator and angiogenic factor, while 15-LOX drives oxidative stress and contributes to plaque destabilization. The PPAR-α pathway emerges as a critical regulator of lipid metabolism and vascular inflammation, with the rs1800206 variant modifying disease susceptibility and therapeutic responses to fibrates. The authors further explore established and novel biomarkers, including high-sensitivity troponin, CK-MB, hs-CRP, and atherogenic lipid profiles, which collectively enhance ACS diagnosis and risk stratification. The integration of these molecular and genetic markers provides a framework for understanding the complex interplay between inflammation, oxidative stress, and metabolic dysregulation in ACS. Therefore, the findings have value in the clinic since they increase therapy choices for PPAR-α and draw attention to the potential for personalized medicine in ACS. This literature review endeavors to push precision medicine for ACS, by reviewing the specific mechanisms of 13-HODE, 15-LOX and PPAR-α polymorphisms and showing how this information can be applied to help patients.

ACAD10 and ACAD11 enable mammalian 4-hydroxy acid lipid catabolism

2025-06-19

Edrees H. Rashan , Abigail K. Bartlett , Daven B. Khana +7 more | Nature Structural & Molecular Biology

Abstract Fatty acid β-oxidation is a central catabolic pathway with broad health implications. However, various fatty acids, including 4-hydroxy acids (4-HAs), are largely incompatible with β-oxidation machinery before being modified. … Abstract Fatty acid β-oxidation is a central catabolic pathway with broad health implications. However, various fatty acids, including 4-hydroxy acids (4-HAs), are largely incompatible with β-oxidation machinery before being modified. Here we reveal that two atypical acyl-CoA dehydrogenases, ACAD10 and ACAD11, drive 4-HA catabolism in mice. Unlike other ACADs, ACAD10 and ACAD11 feature kinase domains that phosphorylate the 4-hydroxy position as a requisite step in converting 4-hydroxyacyl-CoAs into conventional 2-enoyl-CoAs. Through cryo-electron microscopy and molecular modeling, we identified an atypical dehydrogenase binding pocket capable of accommodating this phosphorylated intermediate. We further show that ACAD10 is mitochondrial and necessary for catabolizing shorter-chain 4-HAs, whereas ACAD11 is peroxisomal and enables longer-chain 4-HA catabolism. Mice lacking ACAD11 accumulate 4-HAs in their plasma and females are susceptible to body weight and fat gain, concurrent with decreased adipocyte differentiation and adipokine expression. Collectively, we present that ACAD10 and ACAD11 are the primary gatekeepers of mammalian 4-HA catabolism.

Role of peroxisome proliferator-activated receptor alpha in neurodegenerative diseases and other neurological disorders: Clinical application prospects

2025-06-19

Zijun Wu , Yuying Zhao , Shujing Hao +3 more | Neural Regeneration Research

Abstract Peroxisome proliferator-activated receptor alpha is a member of the nuclear hormone receptor superfamily and functions as a transcription factor involved in regulating cellular metabolism. Previous studies have shown that … Abstract Peroxisome proliferator-activated receptor alpha is a member of the nuclear hormone receptor superfamily and functions as a transcription factor involved in regulating cellular metabolism. Previous studies have shown that PPARα plays a key role in the onset and progression of neurodegenerative diseases. Consequently, peroxisome proliferator-activated receptor alpha agonists have garnered increasing attention as potential treatments for neurological disorders. This review aims to clarify the research progress regarding peroxisome proliferator-activated receptor alpha in nervous system diseases. Peroxisome proliferator-activated receptor alpha is present in all cell types within adult mouse and adult neural tissues. Although it is conventionally believed to be primarily localized in the nucleus, its function may be regulated by a dynamic balance between cytoplasmic and nuclear shuttling. Both endogenous and exogenous peroxisome proliferator-activated receptor alpha agonists bind to the peroxisome proliferator-activated response element to exert their biological effects. Peroxisome proliferator-activated receptor alpha plays a significant therapeutic role in neurodegenerative diseases. For instance, peroxisome proliferator-activated receptor alpha agonist gemfibrozil has been shown to reduce levels of soluble and insoluble amyloid-beta in the hippocampus of Alzheimer’s disease mouse models through the autophagy-lysosomal pathway. Additionally, peroxisome proliferator-activated receptor alpha is essential for the normal development and functional maintenance of the substantia nigra, and it can mitigate motor dysfunction in Parkinson’s disease mouse models. Furthermore, peroxisome proliferator-activated receptor alpha has been found to reduce neuroinflammation and oxidative stress in various neurological diseases. In summary, peroxisome proliferator-activated receptor alpha plays a crucial role in the onset and progression of multiple nervous system diseases, and peroxisome proliferator-activated receptor alpha agonists hold promise as new therapeutic agents for the treatment of neurodegenerative diseases, providing new options for patient care.

Identification of Plasma Free Fatty Acid Carrier Proteins in Mice

2025-06-18

Keigo Tomoo , Yi Zhang , Rodrigo Mohallem +3 more | The FASEB Journal

ABSTRACT Free fatty acid (FFA) transport through the bloodstream had been believed to mainly depend on binding to albumin. However, we recently discovered that albumin knockout (Alb −/− ) mice … ABSTRACT Free fatty acid (FFA) transport through the bloodstream had been believed to mainly depend on binding to albumin. However, we recently discovered that albumin knockout (Alb −/− ) mice still have meaningful levels of FFAs in the bloodstream, indicating the presence of other FFA carrier proteins in plasma. To identify these proteins, we collected plasma from wildtype (WT) and Alb −/− mice. Plasma proteins that can bind to FFAs were isolated by a fatty acid pulldown assay and identified by proteomic analysis. Additionally, plasma proteins were separated by fast protein liquid chromatography (FPLC), and the FPLC fractions were used to measure FFAs, cholesterol, triacylglycerol, and plasma proteins of interest. Furthermore, in silico docking simulations were used to identify potential FFA binding sites on the more highly expressed proteins isolated by the fatty acid pulldown assay to ascertain the likelihood that these proteins may have binding sites for FFA. Proteomic analysis on proteins isolated by the pulldown assay detected 202 proteins, collectively termed the FFA transportome. Examples of highly expressed proteins that showed FFA binding in the assay include albumin, transferrin, and apolipoprotein A‐I. Notably, FFA levels in the FPLC fractions positively correlated with albumin, transferrin, HDL cholesterol, and Apo AI levels. The docking results further suggested that indeed many of the discovered proteins may have FFA binding sites. In conclusion, we elucidated the FFA transportome in mice, and this collection of FFA carrier proteins may facilitate FFA transport through the bloodstream along with albumin.

Nytt fra internasjonal forskning: Omega-3 stimulerer helkroppslig proteinsyntese – men ikke i skjelettmuskulatur

2025-06-17

Martin Norum | Norsk tidsskrift for ernæring

Retraction Note: High levels of fatty acid-binding protein 5 excessively enhances fatty acid synthesis and proliferation of granulosa cells in polycystic ovary syndrome

2025-06-16

Jingyu Liu , Jie Li , Xin Wu +4 more | Journal of Ovarian Research

Characterizing fatty acid oxidation genes in Drosophila

2025-06-16

Juliana Geronazzo , Abigail Heimerl , L Lindell +7 more | G3 Genes Genomes Genetics

Abstract In this study, we leverage the power and tractability of Drosophila genetics to better understand the molecular mechanisms underlying a group of rare genetic diseases known as fatty acid … Abstract In this study, we leverage the power and tractability of Drosophila genetics to better understand the molecular mechanisms underlying a group of rare genetic diseases known as fatty acid oxidation disorders. We use CRISPR-Cas9 to generate mutations in six putative fatty acid oxidation genes in Drosophila, then analyze the phenotypes and acylcarnitine profiles of these flies. We find that while Arc42 and CG4860 are both predicted orthologs of human ACADS, only Arc42 loss of function mirrors the acylcarnitine profile of ACADS loss of function. Acylcarnitine profiles also support our previous identification of Mcad as the likely ACADM ortholog, and reveal the deleterious effects of a single codon deletion in Mtpα (the predicted human HADHA ortholog). Finally, we observe that loss of function in Etf-QO and in CG7834—predicted orthologs of human ETFDH and ETFB, respectively—is homozygous lethal in flies. Producing animal models like these will enable new approaches to studying fatty acid oxidation disease progression, symptomatic variability, and therapeutic intervention.

Peroxisome proliferator-activated receptor antagonists as emerging therapeutics in cancer treatment

2025-06-16

Snehal Misal , Vijay Patil , C. S. Ramaa +1 more | Bioorganic Chemistry

Cancer remains one of the leading causes of mortality worldwide, driving the need for novel therapeutic strategies. Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear hormone receptors that regulate … Cancer remains one of the leading causes of mortality worldwide, driving the need for novel therapeutic strategies. Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear hormone receptors that regulate lipid metabolism, inflammation, and tumor progression. While PPAR agonists have been widely explored for their anticancer potential, recent evidence highlights PPAR antagonists as promising therapeutic candidates. These antagonists selectively modulate oncogenic pathways by disrupting metabolic and signaling networks that support tumor growth, survival, and metastasis. PPARα antagonists, such as N-(2-bromophenyl)-2-[[(3-chlorophenyl)amino]thioxomethyl]acetamide (GW6471) and TPST-1120, impair tumor metabolism and angiogenesis, reducing cancer progression. Their combination with immunotherapy has shown enhanced antitumor effects in preclinical models. PPARβ/δ antagonists, including 4-[3-(4-Acetyl-3-hydroxy-2-propylphenoxy)propoxy]benzoic acid (GSK0660) and methyl 3-(N-(4-(hexylamino)-2-methoxyphenyl)sulfamoyl)thiophene-2-carboxylate (ST247), suppress β-catenin-driven oncogenic transcription, modulating cell proliferation and invasion. PPARγ antagonists, such as 2-Chloro-5-nitro-N-phenylbenzamide (T0070907) and 2-Chloro-5-nitro-N-phenylbenzamide (GW9662), interfere with cancer cell metabolism, apoptosis, and migration, thereby enhancing their antitumor efficacy. Combination strategies involving chemotherapy, radiotherapy, or targeted therapies have shown synergistic effects, improving treatment response and overcoming resistance. Beyond direct tumor suppression, PPAR antagonists modulate immune responses and reshape the tumor microenvironment, offering a multifaceted therapeutic approach. Despite promising results, clinical translation remains limited and requires further studies to improve selectivity, pharmacokinetics, and drug delivery strategies. This review provides a comprehensive analysis of the medicinal chemistry, molecular mechanisms, and pharmacological development of PPAR antagonists, highlighting their potential clinical applications. Future efforts should refine drug design, develop personalized treatments, and conduct well-designed clinical trials to unlock their role in precision oncology.

Effect of saroglitazar on glycaemic parameters: A systematic review and meta‐analysis of randomized controlled trials

2025-06-16

Luis E. Simental‐Mendía , Mario Simental‐Mendía , Laura J. Barragán-Zúñiga +1 more | Diabetes Obesity and Metabolism

Abstract Aims Saroglitazar is a dual peroxisome proliferator‐activated receptor (PPAR), predominantly a PPAR‐α agonist and a moderate PPAR‐γ agonist activity, which has shown positive effects in diabetic dyslipidaemia. However, its … Abstract Aims Saroglitazar is a dual peroxisome proliferator‐activated receptor (PPAR), predominantly a PPAR‐α agonist and a moderate PPAR‐γ agonist activity, which has shown positive effects in diabetic dyslipidaemia. However, its potential anti‐diabetic effect has not been thoroughly investigated, and the data have been inconsistent. Thus, we conducted a meta‐analysis to examine the impact of saroglitazar on glycaemic markers in patients with dyslipidaemia, type 2 diabetes and non‐alcoholic fatty liver disease. Materials and Methods The search strategy was conducted in PubMed, Web of Science, Scopus, ClinicalTrials.gov and Google Scholar databases. Randomized controlled trials reporting changes in glycaemic parameters after saroglitazar therapy were selected. The Cochrane risk‐of‐bias tool for randomized trials version 2 was used to assess the quality of the included studies. For meta‐analysis, a random‐effects model and the generic inverse variance method were conducted. Also, the leave‐one‐out method was applied for the sensitivity analysis. Results A total of 10 clinical trials ( N = 2077; mean age: 49.7 years; 40% female) were included. Regarding the quality of the included studies, two trials had a low risk of bias, seven trials showed some concerns and one study exhibited a high risk of bias. The meta‐analysis of 10 randomized controlled trials showed that saroglitazar significantly reduces fasting glucose (weighted mean difference [WMD]: −12.11 mg/dL, 95% CI: −14.79, −9.43, p < 0.0001, I 2 = 40%), postprandial glucose (WMD: −16.17 mg/dL, 95% CI: −22.29, −10.04, p < 0.0001, I 2 = 0%) and HbA1c (WMD: −0.39%, 95% CI: −0.57, −0.22, p < 0.0001, I 2 = 72%) compared to active control or placebo. However, there was no significant effect on insulin levels (WMD: −1.03 μU/mL, 95% CI: −4.12, 2.06, p = 0.51, I 2 = 37%), HOMA‐IR (WMD: –0.41, 95% CI: −0.86, 0.04, p = 0.07, I 2 = 41%) and C‐peptide (WMD: −0.30 ng/mL, 95% CI: −0.76, 0.15, p = 0.19, I 2 = 0%) after saroglitazar therapy. Conclusions Our results revealed that saroglitazar therapy improves glycaemic parameters through the reduction of fasting glucose, postprandial glucose and HbA1c.

Pivotal role of PPARγ in UTO

2025-06-16

Louise Lloyd | Nature Reviews Urology

Proteomic and metabolic profiling reveals APOE4-dependent shifts in whole brain, neuronal, and astrocytic mitochondrial function and glycolysis

2025-06-16

Colton R Lysaker , Chelsea Johnson , Vivien Csikós +7 more | bioRxiv (Cold Spring Harbor Laboratory)

Apolipoprotein E (APOE) genetic variation is the strongest genetic risk factor for late onset Alzheimers disease (LOAD). Studies on APOE genotype dependent changes have largely focused on amyloid beta aggregation, … Apolipoprotein E (APOE) genetic variation is the strongest genetic risk factor for late onset Alzheimers disease (LOAD). Studies on APOE genotype dependent changes have largely focused on amyloid beta aggregation, disease pathology, and lipid metabolism. Recently, there has been increased interest in the relationship between metabolic function and APOE genetic variation. In this study, we examined how APOE genotype can alter metabolism in the brains of young male and female APOE3 and APOE4 targeted replacement (TR) mice. In combination with this, we also examined cell type-specific differences using induced pluripotent stem cell (iPSC) derived astrocytes and neurons. We found sex and genotype dependent changes to metabolism in the brains of young APOE TR mice. Specifically, APOE4 mice show signs of metabolic stress and compensatory mechanisms in the brain. Using proteomics and stable isotope tracing metabolomics, we found that APOE4 iAstrocytes and iNeurons exhibit signs of inflammation, mitochondrial dysfunction, altered TCA cycle and malate-aspartate shuttle activity, and a metabolic shift toward glycolysis. Taken together, this data indicates APOE4 causes early changes to metabolism within the central nervous system. While this study establishes a relationship between APOE genotype and alterations in bioenergetics, additional studies are needed to investigate underlying mechanisms.

Pseudolaric Acid B Alleviates Non-alcoholic Fatty Liver Disease by Targeting PPARα to Regulate Lipid Metabolism and Promote Mitochondrial Biogenesis

2025-06-14

Shu-Yan Liu , Xiaowei Zhang , Gai Gao +7 more | Chinese Journal of Integrative Medicine

Predicting peroxisome proliferator-activated receptor gamma potency of small molecules: a synergistic consensus model and deep learning binding affinity approach powered by Enalos Cloud Platform

2025-06-14

Μαρία Αντωνίου , Konstantinos D. Papavasileiou , Andreas Tsoumanis +2 more | Molecular Diversity

A guide to selecting high-performing antibodies for Stearoyl-CoA desaturase (SCD1) (UniProt ID: O00767) for use in western blot, immunoprecipitation, and immunofluorescence

2025-06-13

Vera Ruíz Moleón , Charles Alende , Maryam Fotouhi +3 more | F1000Research

<ns5:p>The enzyme stearoyl-CoA desaturase (SCD1) is a modulator of lipid metabolism by catalyzing the biosynthesis of mono-unsaturated fatty acids from saturated fatty acids. Understanding the specific mechanisms by which SCD1 … <ns5:p>The enzyme stearoyl-CoA desaturase (SCD1) is a modulator of lipid metabolism by catalyzing the biosynthesis of mono-unsaturated fatty acids from saturated fatty acids. Understanding the specific mechanisms by which SCD1 plays in health and disease can provide novel insides in therapeutic targets, a process that would be facilitated by the availability of high-quality antibodies. Here we have characterized nine SCD1 commercial antibodies for western blot, immunoprecipitation, and immunofluorescence using a standardized experimental protocol based on comparing read-outs in knockout cell lines and isogenic parental controls. These studies are part of a larger, collaborative initiative seeking to address antibody reproducibility issues by characterizing commercially available antibodies for human proteins and publishing the results openly as a resource for the scientific community. While use of antibodies and protocols vary between laboratories, we encourage readers to use this report as a guide to select the most appropriate antibodies for their specific needs.</ns5:p>

1873-LB: Genetically Determined PPARA Expression Modulates Fenofibrate Response on Lipid Profile—A Pharmacogenetic Trial

2025-06-13

MARIO LUCA MORIERI , Mauro Giordano , Carlo Fagarazzi +7 more | Diabetes

Introduction and Objective: We showed that genetic variability in the PPARA region influences the effectiveness of the PPAR-α agonist fenofibrate on CVD and diabetic retinopathy (DR) progression, even in subjects … Introduction and Objective: We showed that genetic variability in the PPARA region influences the effectiveness of the PPAR-α agonist fenofibrate on CVD and diabetic retinopathy (DR) progression, even in subjects without atherogenic dyslipidemia. Evidence suggests that higher genetically determined PPARA expression (Genetic Score (eQtGS) of PPARA retinal expression) may contribute to greater fenofibrate benefit. Here, we tested, in a pharmacogenetic trial, whether PPARA eQtGS influences fenofibrate’s effect on lipid and apolipoprotein profiles in statin-treated subjects with on-target lipid levels. Methods: We enrolled adult patients with type 2 diabetes, stable statin treatment, LDL-C &lt;100 mg/dL, triglycerides &lt;200 mg/dl, HbA1c &lt;8%, and eGFR &gt;60 mL/min, to be randomized to 12 weeks of fenofibrate or placebo. Lipid profile, apolipoproteins, transaminases, creatinine, CPK, and CRP were assessed. The eQtGS was derived from the EyeGEx database. Results: A total of 180 subjects (mean age: 66 years, 23% female, 33% obese, 23% with prior CAD, HbA1c: 6.6%) completed the study. All were on statins, mean LDLc was 62 mg/dl and triglycerides 102 mg/dl. Fenofibrate significantly reduced triglycerides (-20.7 mg/dL) and ApoCIII (-1.56 mg/dL) while increasing LDL-C (+4.62 mg/dL), ApoAII (+8.5 mg/dL), and creatinine (+0.14 mg/dL, all p&lt;0.05). PPARA eQtGS significantly modulated fenofibrate’s effects on total and LDL-C, ApoB (higher PPARA eQtGS being associated with lower levels of LDL-C and ApoB after fenofibrate treatment). A significant positive eQtGS by fenofibrate interaction was found on fenofibrate-induced transaminase elevations. Conclusion: These precision medicine finding supports the concept that genetically determined PPARA expression affects fenofibrate response. Nonetheless the observed differences are unlikely to fully explain the large CVD and DR effect seen in previous studies. Further research is needed to dissect additional mechanisms and tissue-specific eQtGS effects. Disclosure M. Morieri: Advisory Panel; Amgen Inc. Speaker's Bureau; AstraZeneca, Novo Nordisk, Daiichi Sankyo, Merck Sharp & Dohme Corp, Servier Laboratories, Novartis Pharmaceuticals Corporation, Lilly Diabetes. M. Giordano: None. C. Fagarazzi: None. C. Boscaro: None. M. Marassi: None. E. Iori: None. F. Amendolagine: None. A. Rodella: None. L. Migliozzi: None. C. Pipino: None. C. Zambon: None. A. Doria: Research Support; Abbott, Lexicon Pharmaceuticals, Inc, Dexcom, Inc. M. Albiero: None. G. Fadini: Speaker's Bureau; AstraZeneca. Advisory Panel; Boehringer-Ingelheim. Speaker's Bureau; Menarini. Advisory Panel; Lilly Diabetes. Consultant; Lilly Diabetes. Speaker's Bureau; Lilly Diabetes. Advisory Panel; Novo Nordisk. Speaker's Bureau; Novo Nordisk. Advisory Panel; Sanofi. Speaker's Bureau; Sanofi. Funding Italian Ministry of Health Grant “Ricerca Finalizzata 2019” (GR-2019-12369702)

342-OR: Cell-State Dependent Regulation of PPARγ Signaling by the Transcription Factor ZBTB9 in Adipocytes

2025-06-13

Xuan Xu , Jeremiah Ockunzzi , David A. Buchner | Diabetes

Introduction and Objective: ZBTB9 is a widely expressed but poorly studied transcription factor that interacts with the key adipocyte regulator PPARγ. In addition, genetic variants in ZBTB9 are associated with … Introduction and Objective: ZBTB9 is a widely expressed but poorly studied transcription factor that interacts with the key adipocyte regulator PPARγ. In addition, genetic variants in ZBTB9 are associated with BMI, T2D risk, and HbA1c levels. Thus, we sought to investigate the role of Zbtb9 in adipocyte function and metabolic health. Methods: We combined genomic, biochemical, and cell biology approaches in both human and mouse adipocyte cell lines as well as in vivo studies of a floxed Zbtb9 allele to investigate the function of Zbtb9. Results: We discovered that Zbtb9 deficiency in adipocytes decreased PPARγ activity and protein level. In contrast, Zbtb9 deficiency in preadipocytes increased PPARγ levels and enhanced adipogenesis. Transcriptomic analyses of Zbtb9 deficient preadipocytes revealed that the E2F pathway was among the most upregulated pathways, and RB phosphorylation (pRB) was likewise increased, which in turn regulates E2F activity. Inhibition of the E2F pathway blocked the effects of Zbtb9 deficiency on adipogenesis. Collectively, these results demonstrate that Zbtb9 inhibits adipogenesis as a negative regulator of Pparg expression via pRB-E2F signaling in preadipocytes while positively regulating PPARγ signaling in mature adipocytes by increasing levels of PPARγ protein. Adipocyte-specific deletion of Zbtb9, using a newly generated floxed allele, resulted in impaired glucose homeostasis without altering fat pad morphology, particularly in mice fed a high-fat diet, whereas deletion of Zbtb9 in preadipocytes altered fat pad morphology resulting in smaller adipocytes, confirming the in vivo importance of Zbtb9 in metabolic health. Conclusion: Our findings reveal cell-state dependent roles of ZBTB9 in adipocytes, identifying a new molecule that regulates adipocyte biology as both a positive and negative regulator of PPARγ signaling depending on the cellular context, and thus may be important in the pathogenesis of obesity and T2D. Disclosure X. Xu: None. J. Ockunzzi: None. D. Buchner: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (DK119305)

1610-P: Oxymatrine Regulates Lipid Metabolism and Improves Oxidative Stress to Alleviate Nonalcoholic Fatty Liver Disease via PPARα-ApoA1/CPT1A Pathway—Combining Transcriptomics and Metabolomics

2025-06-13

Luping Ren , Xuehua Liu , Feng-Hua Song +2 more | Diabetes

Introduction and Objective: Nonalcoholic fatty liver disease is the most common cause of chronic liver disease worldwide. Oxymatrine is a potent monomeric alkaloid extracted from the root of Sophora flavescens. … Introduction and Objective: Nonalcoholic fatty liver disease is the most common cause of chronic liver disease worldwide. Oxymatrine is a potent monomeric alkaloid extracted from the root of Sophora flavescens. This study aimed to explore the molecular mechanism of the improvement of oxymatrine on the liver of rats with nonalcoholic fatty liver disease induced by a high-fat and high-fructose diet by integrating transcriptomics and metabolomics. Methods: Wistar rats were fed a high-fat, high-fructose diet for 8 weeks and then gavaged with oxymatrine for the last 4 weeks. Biochemical indices and pathological changes of rats in each group were detected, and transcriptomics and metabolomics methods were used to analyze the changes in gene expression and metabolites in the liver and serum of rats, respectively. Results: Oxymatrine significantly reduced liver lipid accumulation and improved oxidative stress. Four differentially expressed genes, namely Apoa1, Cpt1a, Apob and Fga, were screened and identified through liver transcriptomics, revealing that oxymatrine inhibits lipid accumulation mainly by activating the PPARα-Cpt1a/Apoa1 pathway. In addition, metabolomic analysis showed that differential metabolites were mainly concentrated in glucagon signaling pathway, regulation of lipolysis in adipocytes, and signaling pathways related to lipid metabolism and oxidative stress, such as metabolism and sphingomyelin signaling pathways, and serum Ascorbic acid, Ergothioneine, s-methy GSH and other antioxidants were significantly up-regulated after oxymatrine intervention. Conclusion: Oxymatrine mainly inhibits lipid accumulation and improves oxidative stress by activating the PPARα-Apoa1/Cpt1a pathway, thereby improving non-alcoholic fatty liver disease. Disclosure L. Ren: None. X. Liu: None. F. Song: None. Y. Pan: None. J. Zhang: None. Funding Natural Science Foundation of Hebei Province (H2022307033)

1552-P: The Role of PPARα in Modulating Macrophage Polarization during Periodontitis in Diabetes

2025-06-13

Anqun Hu , Ying Chen | Diabetes

Introduction and Objective: Periodontitis (PD), a chronic inflammatory condition, is a leading cause of tooth loss and jawbone deterioration and is associated with an increased risk of diabetes. The persistent … Introduction and Objective: Periodontitis (PD), a chronic inflammatory condition, is a leading cause of tooth loss and jawbone deterioration and is associated with an increased risk of diabetes. The persistent inflammation in PD results from an imbalance between pro-inflammatory (M1) and anti-inflammatory (M2) macrophages, contributing significantly to tissue destruction. This study investigates the role of peroxisome proliferator-activated receptor alpha (PPARα), a nuclear hormone receptor, in regulating macrophage polarization during PD, particularly in the context of diabetes. Methods: In vivo: PD was induced in diabetic (db/db) mice. PPARα expression levels were analyzed, and the effects of PPARα activation on periodontal inflammation and alveolar bone loss were assessed.In vitro: Macrophages were treated with Porphyromonas gingivalis (P.g.) lipopolysaccharide (LPS) and analyzed for PPARα activity under normal and high-glucose conditions. M1 and M2 macrophage markers, including CD14 and IL-10, were measured following PPARα agonist treatment. Results: PPARα expression was markedly reduced in diabetic animals with PD. Lack of PPARα exacerbated periodontal inflammation and alveolar bone loss in db/db mice, whereas activation of PPARα ameliorated these effects. LPS treatment inhibited PPARα activity in a dose-dependent manner, an effect partially reversed by PPARα agonists. However, the reversal was less effective under high-glucose conditions. PPARα activation reduced M1 macrophage marker expression (CD14) and increased M2 macrophage marker expression (IL-10) in vitro. Conclusion: PPARα plays a critical role in modulating macrophage polarization during PD, particularly in diabetes. Activation of PPARα attenuates inflammation and promotes a shift from pro-inflammatory to anti-inflammatory macrophages, highlighting its therapeutic potential for managing PD and its complications in diabetic individuals. Disclosure A. Hu: None. Y. Chen: None.

482-P: Eicosapentaenoic Acid (EPA) Alleviates LPS-Induced Oxidative Stress via the PPARα-NF-κB Axis

2025-06-13

Haya Alabduljader , Halemah AlSaeed , Amenah Alrabeea +3 more | Diabetes

Introduction and Objective: Metabolic endotoxemia, fueled by lipopolysaccharide (LPS) translocation, promotes chronic inflammation and insulin resistance in obesity and type 2 diabetes. Eicosapentaenoic acid (EPA/C20:5) exhibits anti-inflammatory and antioxidative effects, … Introduction and Objective: Metabolic endotoxemia, fueled by lipopolysaccharide (LPS) translocation, promotes chronic inflammation and insulin resistance in obesity and type 2 diabetes. Eicosapentaenoic acid (EPA/C20:5) exhibits anti-inflammatory and antioxidative effects, yet its precise mechanism against LPS-induced oxidative stress in macrophages remains unclear. This study investigates EPA’s protective role via the FABP5/PPARα/NF-κB axis. Methods: THP-1 monocytes were differentiated into macrophages and pretreated with EPA or vehicle for 24 hours, followed by overnight LPS stimulation. Gene expression was analyzed by TaqMan; protein levels by Western blot, flow cytometry, and ELISA. Mitochondrial membrane potential and ROS were measured with JC-1 and DCFH-DA assays, respectively. Pharmacological inhibition of PPARα was performed with GW9662. Results: EPA pretreatment significantly dampened LPS-induced inflammatory responses, as evidenced by reduced IL-1β and IL-6 expression, decreased IL-1β secretion, and a lower percentage of HLA-DR+ macrophages. Concomitantly, ER stress markers (ATF4, DDIT3, HSPA5/GRP78, BIP, and CHOP) were downregulated at both gene and protein levels. EPA also mitigated oxidative stress, indicated by lower expression of HIF1α, decreased ROS levels, and preserved mitochondrial membrane potential. Mechanistically, EPA stimulated PPARα and FABP5 expression while inhibiting NF-κB activation, independent of TLR4-IRF5 signaling. Notably, blocking PPARα with GW9662 abolished these protective effects, underscoring the necessity of PPARα activation in EPA-mediated cytoprotection. Conclusion: EPA ameliorates LPS-induced oxidative stress and inflammation in macrophages by activating PPARα and FABP5 while inhibiting NF-κB, offering a potential therapeutic strategy to counter inflammation in metabolic disorders. Disclosure H. Alabduljader: None. H. AlSaeed: None. A. Alrabeea: None. F. Almulla: None. R. Ahmad: None. F. Alrashed: None. Funding Kuwait Foundation for the Advancement of Sciences (KFAS) RA CB-2019-002

Human CD36: Gene Regulation, Protein Function, and Its Role in Atherosclerosis Pathogenesis

2025-06-13

Monika Rać | Genes

Human CD36 plays an important role in ligand binding, signalling, cell adhesion, and the regulation of angiogenesis. As a scavenging receptor, it is responsible for clearing long-chain fatty acids (LCFAs) … Human CD36 plays an important role in ligand binding, signalling, cell adhesion, and the regulation of angiogenesis. As a scavenging receptor, it is responsible for clearing long-chain fatty acids (LCFAs) and removing approximately 50% of oxidised low-density lipoprotein (ox-LDL) from plasma. The CD36 gene is alternatively spliced. It has several alternative promoters and first exons. The alternative transcripts are expressed in multiple tissues, and their expression patterns are highly variable. The molecular mechanisms that regulate CD36 gene expression are complex and reflect its multifunctional role in different tissues. CD36 activity has been linked to several metabolic processes, such as inflammation, angiogenesis, phagocytosis, and energy homeostasis. CD36 plays a key role in regulating vascular and cardiovascular health and in the pathogenesis of atherosclerosis. CD36 gene mutations in the Caucasian population are rare. Hence, it is extremely difficult to recruit a statistically significant group of CAD patients with these mutations. Nevertheless, this population is largely at risk of cardiovascular disease. Atherosclerosis is a multifactorial disease, but the role of the CD36 receptor in the development of ox-LDL is extremely important. This review aims to introduce readers to issues related to the relationship between CD36 and CAD. The activity of this receptor should be considered when exploring treatment options for atherosclerosis-related complications.

1825-P: Potentiation of Glucose-Stimulated Insulin Secretion by Free Fatty-Acid Receptor 4 Involves Distinct Mechanisms in Mouse vs. Human Islets

2025-06-13

LAURA REININGER , AMÉLIA BOUABCHA , MUHAMMAD H. REHMAN +7 more | Diabetes

Introduction and Objective: The long-chain fatty-acid receptor FFA4 exerts beneficial effects on glucose homeostasis and is considered a potential therapeutic target for type 2 diabetes. We previously showed in mouse … Introduction and Objective: The long-chain fatty-acid receptor FFA4 exerts beneficial effects on glucose homeostasis and is considered a potential therapeutic target for type 2 diabetes. We previously showed in mouse islets that FFA4 activation potentiates glucose-stimulated insulin secretion indirectly via inhibition of somatostatin (SST) secretion from δ cells. However, the mechanism of action of FFA4 in human islets remains unknown. Here, we investigated the mechanism of FFA4 action in mouse islets and explored the hypothesis that FFA4 agonists directly stimulate insulin secretion in human β cells. Methods: One-hour static incubations were performed on isolated mouse and human islets exposed to the selective FFA4 agonist CpdA (20 μM). Insulin and SST were assessed by radioimmunoassay. Data are expressed as mean ± SEM. Significance was tested using two-way ANOVA with post-hoc adjustment (Tukey test). Results: In mouse islets, CpdA potentiated glucose-induced insulin secretion (2.0 ± 0.3 fold increase vs. glucose alone; n=6; p&lt;0.05) and decreased SST secretion (34 ± 5 pM vs. 58 ± 7 pM in glucose alone; n=7; p&lt;0.001). CpdA did not affect insulin secretion in SST-deficient islets (1.1 ± 0.1 fold increase vs. glucose alone; n=9; ns). As we previously showed that FFA4 does not couple to Gαi/o, we asked whether it couples to Gαz in δ cells. CpdA did not reduce SST secretion in Gnaz knockout (35 ± 23 pM vs. 47 ± 16 pM in glucose alone; n=8; ns) islets. In human islets, in line with the elevated expression of FFAR4 in β cells, CpdA potentiated insulin secretion (1.8 ± 0.2 fold increase vs. glucose alone; n=3; p&gt;0.05) but had no effect on SST secretion (67 ± 12 pM vs. 74 ± 14 pM in glucose alone; n=4; ns). Conclusion: Our data suggest distinct mechanisms of action whereby FFA4-Gαz coupling indirectly increases insulin secretion via inhibition of SST secretion in rodent’s δ cells, whereas in humans, FFA4 activation in β cells directly increases insulin secretion. Disclosure L. Reininger: None. A. Bouabcha: None. M.H. Rehman: None. S. Ferragne: None. C. Tremblay: None. M. Ethier: None. J. Ghislain: None. M.E. Kimple: None. M.O. Huising: Research Support; Thermo Fisher. V. Poitout: Research Support; Biodexa. Funding NIH (R01DK132597)

A Quality by Design Driven RP-HPLC Method for the Assay of Lobeglitazone & Glimepiride and In-silico Admet Studies

2025-06-12

Challa Gangu Naidu , Jagadeesh Adari , Vara Prasada Rao Kollabathula +2 more | Current Trends in Biotechnology and Pharmacy

Atheroprotection mediated by hepatic PPARα is linked to its anti-inflammatory, but not lipid-lowering, properties

2025-06-12

Karina Huynh | Nature Reviews Cardiology

Microbodies (Peroxisomes and Microperoxisomes)

2025-06-11

Giovanna M. Crisi | CRC Press eBooks

A Review on Analytical Methods for Determination of Pioglitazone with RBG and White Analysis

2025-06-05

Anusha Boggavarapu , Swetha Vegesna , V Sahithi | Journal of Pharma Insights and Research.

Modern pharmaceutical analysis requires precise, accurate, and environmentally friendly methods for drug determination. The presented work discusses about analytical techniques for quantifying pioglitazone, its metabolites, and combinations with other anti-diabetic … Modern pharmaceutical analysis requires precise, accurate, and environmentally friendly methods for drug determination. The presented work discusses about analytical techniques for quantifying pioglitazone, its metabolites, and combinations with other anti-diabetic medications. The main analytical techniques discussed include Reversed-Phase High-Performance Liquid Chromatography (RP-HPLC), UV spectroscopy, Micellar Electrokinetic Chromatography (MEKC), Liquid Chromatography-Mass Spectrometry (LC-MS/MS), and High-Performance Thin-Layer Chromatography (HPTLC). Each method demonstrates unique advantages in sensitivity, specificity, and applicability across various matrices, from pharmaceutical formulations to biological samples. The RP-HPLC methods show excellent linearity (100-600 μg/ml) and precision (RSD ≤ 2%). UV spectroscopic methods offer simplicity with detection limits as low as 0.0002 μg/ml. LC-MS/MS techniques provide superior sensitivity for metabolite detection in plasma samples. The integration of RGB (Red, Blue, Green) and White analysis represents an innovative approach, incorporating environmental considerations while maintaining analytical performance. The use of eco-friendly solvents, such as ethanol, demonstrates the evolution toward sustainable analytical practices. The validation parameters, including linearity, accuracy, precision, detection limits, and robustness, provide essential guidance for method selection in quality control and pharmacokinetic studies. The reported methods offer reliable solutions for pioglitazone analysis while overcoming the environmental concerns through the principles of green chemistry

Seizures in childhood cerebral adrenoleukodystrophy

2025-06-05

| Developmental Medicine & Child Neurology