The mechanisms of action of PPARs.

doi:10.1146/ANNUREV.MED.53.082901.104018

Paper

The mechanisms of action of PPARs.

Published 2002 · J. Berger, D. Moller

Annual review of medicine

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2,529

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125

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Abstract

The peroxisome proliferator-activated receptors (PPARs) are a group of three nuclear receptor isoforms, PPAR gamma, PPAR alpha, and PPAR delta, 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.

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Study Snapshot

PPARs play a crucial role in lipid metabolism and play a role in the etiology and treatment of various chronic diseases, including atherosclerosis, inflammation, cancer, infertility, and demyelination.

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

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The mechanisms of action of PPARs.

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Acrp30 is a potent insulin enhancer that links adipose tissue and whole-body glucose metabolism, reducing glucose levels without increasing insulin levels.

Oxidized Alkyl Phospholipids Are Specific, High Affinity Peroxisome Proliferator-activated Receptor γ Ligands and Agonists*

Oxidized alkyl phospholipids in oxLDL are specific, high affinity ligands and agonists for PPAR, inducing PPAR-responsive genes.

Thiazolidinediones increase plasma-adipose tissue FFA exchange capacity and enhance insulin-mediated control of systemic FFA availability.

Thiazolidinediones improve lipid metabolism, reduce hypertriglyceridemia, and enhance metabolic flexibility by improving glucoregulation and using FFAs during fasting.

Peroxisome Proliferator-activated Receptor-γ Ligands Inhibit Adipocyte 11β-Hydroxysteroid Dehydrogenase Type 1 Expression and Activity*

PPAR agonists reduce 11-HSD-1 expression in adipocytes, potentially contributing to their beneficial effects in diabetes by reducing corticosterone levels.

A selective peroxisome proliferator-activated receptor δ agonist promotes reverse cholesterol transport

GW501516, a selective PPAR agonist, effectively increases reverse cholesterol transport and decreases cardiovascular disease associated with metabolic syndrome X.

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Troglitazone inhibits early atherosclerotic lesion formation in male low density lipoprotein receptor-deficient mice, potentially due to direct effects of PPAR&ggr; activation in the artery wall.

Comprehensive Messenger Ribonucleic Acid Profiling Reveals That Peroxisome Proliferator-Activated Receptor γ Activation Has Coordinate Effects on Gene Expression in Multiple Insulin-Sensitive Tissues.

PPAR activation stimulates gene expression in multiple insulin-sensitive tissues, reducing glucose and triglyceride levels in type 2 diabetes patients.

PPAR δ agonists stimulate oligodendrocyte differentiation in tissue culture

PPAR agonists accelerate oligodendrocyte differentiation in primary and enriched cultures, potentially increasing cell survival and preventing cell death.

Troglitazone Inhibits Atherosclerosis in Apolipoprotein E–Knockout Mice: Pleiotropic Effects on CD36 Expression and HDL

Troglitazone effectively inhibits atherosclerosis in apolipoprotein E-knockout mice by modulating metabolic conditions and arterial wall cell functions.

Citations

A transcription network underlies the dual genomic coordination of mitochondrial biogenesis

A transcription network reveals the logic of mitochondrial biogenesis regulation, with CG1603 playing a crucial role in coordinating nuclear and mitochondrial genome activities.

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Targeting molecular mechanisms in fibrosis through therapeutic strategies has shown promising results in clinical trials, improving organ function and reducing fibrotic lesions.

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Pterocarposide, Sabioside, and Pterostilbene show potential as oral drugs for managing non-insulin dependent diabetes mellitus (NIDDM) through PPAR agonism.

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PPAR agonists show promise in improving metabolic, hepatic, and cardiovascular health in patients with metabolic dysfunction-associated steatotic liver disease.

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This study explores the kinetic features of ligands targeting nuclear receptors, revealing that protein structure conservation is the primary factor influencing pathway selection, potentially aiding drug development through better kinetic properties.

PPARA variant rs1800234 had a dose dependent pharmacogenetics impact on the therapeutic response to chiglitazar.

The PPARA variant rs1800234 has a dose-dependent pharmacogenetic impact on the therapeutic response to chiglitazar, potentially serving as a biomarker for the chosen dose of chiglitazar in the future.

PPARα exacerbates Salmonella Typhimurium infection by modulating the immunometabolism and macrophage polarization

PPAR plays a crucial role in Salmonella Typhimurium infection by modulating lipid metabolism and macrophage polarization, potentially reducing inflammation and bacterial spread.