The role of PPARs in atherosclerosis

doi:10.1016/S1471-4914(02)02385-7

Trends in Molecular Medicine

Volume 8, Issue 9, 1 September 2002, Pages 422-430

https://doi.org/10.1016/S1471-4914(02)02385-7 Get rights and content

Abstract

Peroxisome proliferator-activated receptors (PPARs) are lipid-activated transcription factors that regulate lipid and lipoprotein metabolism, glucose homeostasis and inflammation. The PPAR family consists of three proteins, α, β/δ and γ. Recent data suggest that PPARα and γ activation decreases atherosclerosis progression not only by correcting metabolic disorders, but also through direct effects on the vascular wall. PPARs modulate the recruitment of leukocytes to endothelial cells, control the inflammatory response and lipid homeostasis of monocytes/macrophages and regulate inflammatory cytokine production by smooth muscle cells. Experiments using animal models of atherosclerosis and clinical studies in humans strongly support an anti-atherosclerotic role for PPARα and γ in vivo. Thus, PPARs remain attractive therapeutic targets for the development of drugs used in the treatment of chronic inflammatory diseases such as atherosclerosis. Future research will aim for the development of more potent drugs with co-agonist activity on PPARα, PPARβ/δ and/or PPARγ as well as tissue and target gene-selective PPAR receptor modulators (SPPARMs).

Section snippets

PPARs and the recruitment of leukocytes in the early atherosclerotic lesion

PPARs interfere with the earliest processes in atherogenesis, which consist of leukocyte chemoattraction and recruitment to atherosclerotic lesions. PPARs modulate the production of chemokines, the expression of chemokine receptors as well as adhesion molecules in endothelial cells (EC), T cells and monocytes. In ECs, glitazones inhibit the expression of the chemotactic protein monocyte-chemoattractant protein-1 (MCP-1) 8., 9.. Whereas PPARα agonists stimulate basal expression of MCP-1 by human

PPARs and local immune responses

Accumulating evidence indicates that the atherosclerotic process implicates a local immune response characterized by the recruitment, activation and proliferation of various cells of the immune system, including T cells and dendritic cells (DCs). In humans and murine models of atherosclerosis, the colocalization of activated T cells and DCs in atherosclerotic lesions suggests that cellular immunity plays an important role in the pathophysiology of this disease 28., 29.. It has been shown in

PPARs, lipid accumulation and reverse cholesterol transport

After recruitment in the subendothelial region of the artery, monocytes differentiate into macrophages and accumulate lipids to form foam cells. To enter macrophages, LDL must be modified (e.g. through oxidation or glycosylation). Reactive oxygen species (ROS) can induce the oxidative modification of LDL. Superoxide anion (O₂·⁻) might furthermore promote atherogenesis by inducing hypertension and inflammation via NF-κB activation [25]. PPARα and γ activators increase the expression of the

PPARs and local inflammation

ECs, T cells, macrophages and SMCs are believed to contribute to the local inflammatory response by acquiring a pro-inflammatory phenotype. The effects of PPARγ ligands on the inflammation response of macrophages have been well studied, but the role of PPARγ therein is still under debate as the effects are most pronounced with the least selective and active PPARγ agonist, 15d-PGJ₂ (reviewed in Ref. [52]) and are also observed in PPARδ-deficient mice [53]. The role of PPARα in inflammatory

PPARs and fibrous cap development

In middle-advanced stages of atherosclerosis, SMCs proliferate and produce extracellular matrix (ECM) components, thus leading to the formation of a fibrous plaque (fibroatheroma). PPARγ ligands inhibit the proliferation and the migration of vascular SMCs (VSMC), a phenomenon that might be of particular relevance for restenosis prevention 58., 59., 60.. Wakino et al. [61] have demonstrated that proliferation is inhibited most likely by blocking crucial events in G1→S transition, such as

PPARs and plaque stability

The evolution of atherosclerosis to thrombus-provoked coronary events principally depends on plaque stability. Unstable plaques are prone to rupture leading to thrombus formation and vessel wall occlusion. Maintenance of a stable fibrous cap mainly reflects a balance between ECM production and degradation. Troglitazone reduces gene expression of osteopontin, an ECM component synthesized by macrophages in atherosclerotic plaques [71]. Moreover, PPARα and γ ligands repress gene transcription 26.,

PPARs and thrombosis

PPARs also modulate platelet aggregation, an initiating event of atherothrombosis at the ruptured plaque. In rat macrophages, thromboxane synthase (TXS) is inhibited at the transcriptional level by PPARγ, interacting with the transcription factor NRF2 (nuclear factor-E2-related factor 2) [82]. In VSMCs, PPARγ activators inhibit expression of the thromboxane receptor (TXR) [66]. Thus, PPARγ activation results in a diminished synthesis and action of thromboxane A2, which is a potent inducer of

PPARs and acute-phase proteins

Acute-phase proteins are established risk factors for cardiovascular diseases. They are synthesized by the liver during the inflammation reaction. Fenofibrate significantly lowers plasma levels of C-reactive protein (CRP), a complement activator and an inducer of MCP-1 expression in ECs, and fibrinogen, a procoagulant factor [54]. In mice, fibrates decrease plasma fibrinogen levels in a PPARα-dependent manner [84]. PPARα activators repress human fibrinogen gene expression in human hepatocytes

Anti-atherosclerotic effects of PPARs: results from in vivo studies

Compelling evidence for a regulatory role for PPARs in atherogenesis in vivo comes from studies in animal models of atherosclerosis and human clinical trials. In different experimental models of atherosclerosis, PPARγ ligands prevent the progression of atherosclerotic lesions, with a concomitant decrease of macrophage accumulation in the plaque 15., 19., 87.. Glitazones act by reducing monocyte/macrophage homing to atherosclerotic plaques by inhibiting fatty streak formation, improving glucose

Concluding remarks

PPARs play a crucial role in lipid and lipoprotein metabolism as well as in glucose homeostasis. Considerable evidence indicates that PPARα and PPARγ have beneficial effects in inflammatory diseases, including atherosclerosis. These PPARs regulate cytokine production, adhesion molecule expression on endothelial cells, fibrinolysis and modulate macrophage functions. Interestingly, PPARβ/δ, whose function is still not well understood, has been recently implicated in the regulation of macrophage

Acknowledgements

C.D. was supported by a fellowship from ARC (Association pour la Recherche sur le Cancer) and G.C. was supported by grants from European Community (grant QLRT-1999–01007).

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Plasma lipids are modulated by gene variants and many environmental factors, including diet-associated weight gain. However, understanding how these factors jointly interact to influence molecular networks that regulate plasma lipid levels is limited. Here, we took advantage of the BXD recombinant inbred family of mice to query weight gain as an environmental stressor on plasma lipids. Coexpression networks were examined in both nonobese and obese livers, and a network was identified that specifically responded to the obesogenic diet. This obesity-associated module was significantly associated with plasma lipid levels and enriched with genes known to have functions related to inflammation and lipid homeostasis. We identified key drivers of the module, including Cidec, Cidea, Pparg, Cd36, and Apoa4. The Pparg emerged as a potential master regulator of the module as it can directly target 19 of the top 30 hub genes. Importantly, activation of this module is causally linked to lipid metabolism in humans, as illustrated by correlation analysis and inverse-variance weighed Mendelian randomization. Our findings provide novel insights into gene-by-environment interactions for plasma lipid metabolism that may ultimately contribute to new biomarkers, better diagnostics, and improved approaches to prevent or treat dyslipidemia in patients.
Novel dual PPARα/γ agonists protect against liver steatosis and improve insulin sensitivity while avoiding side effects
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Insulin resistance is a feature of type 2 diabetes mellitus (T2D), and is strongly interconnected with non-alcoholic fatty liver disease (NAFLD). Peroxisome-proliferator activated receptor gamma (PPARγ) and peroxisome-proliferator activated receptor alpha (PPARα) are master regulators of insulin sensitivity and lipid metabolism, respectively. Thiazolidinediones (TZDs) such as pioglitazone, which target PPARα/γ, are highly effective at treating insulin resistance and NAFLD, but their clinical utility has been restricted by side effects such as weight gain, adipocyte hypertrophy and fluid retention. Therefore, there is urgent need for new safer and effective drugs. Thus, we aimed to develop novel dual PPARα/γ agonists to avoid their known side effects while preserving their overall therapeutic effects. Here, we show that our novel agonists G4 and G5 strongly stimulate glucose transporter 4 (GLUT4) translocation to the cell membrane in skeletal muscle cells, and manifest weaker lipogenic effect in adipocytes. Moreover, G4 and G5 improve systemic glucose metabolism, hyperinsulinemia, hyperlipidemia, and markers of liver injury in high fructose diet-induced insulin resistant rats. Mechanistic studies revealed that G4 and G5 enhance GLUT4, and AMPK in skeletal muscle and protect against liver steatosis by upregulating PPARα and improve whole-body insulin sensitivity by increasing PPARγ. Despite this increase in PPARγ activity, G4 and G5 inhibit the unwanted side effects such as weight gain due to adiposity, hypertrophy of adipocytes, and fluid retention unlike TZDs. These findings identify G4 and G5 as promising dual PPARα/γ agonists for the treatment of NAFLD and insulin resistance with improved safety.
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Eriobotrya japonica leaf triterpenoid acids ameliorate metabolic syndrome in C57BL/6J mice fed with high-fat diet
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Citation Excerpt :
PPAR-γ has a variety of important physiological activities. PPAR-γ activation can promote the clearance of fatty acids, reduce the levels of TNF-α and leptin, down-regulate the expression of phosphodiesterase, and reduce blood glucose [41]. PPAR-γ activation can also promote the expression of GLUT4 and PI3K [42], ameliorate insulin signaling, and insulin resistance.
It has been demonstrated in some studies that triterpenoid acid extract fromEriobotrya japonica leaf is beneficial to prevent hyperlipidemia or insulin resistance. However, the effect of triterpenoid acids in Eriobotrya japonica leaf on a series of typical symptoms of metabolic syndrome (MetS) has been rarely studied systematically. Therefore, the present study aims to systematically evaluate the effect of Eriobotrya japonica leaf triterpenoid acids (ELTA) on MetS and explore its potential mechanism.
ELTA (HPLC purity 95.2 %) was prepared and administered orally (200 mg/kg) to C57BL/6 J mice fed with a high-fat diet (HFD) for 12 weeks. Pioglitazone (30 mg/kg) was used as a positive control drug. Food intake, body weight, total lipid in feces, lipid profiles, inflammatory factors in serum, hepatic glutathione, and lipid peroxide were measured. Oral glucose tolerance test (OGTT) and insulin tolerance test (ITT) were performed to evaluate insulin sensitivity. RT-qPCR and molecular docking were performed to explore the potential mechanism.
ELTA administration reduced body weight gain, relative liver weight, and relative visceral adipose weight. The levels of serum total cholesterol, triglycerides, low-density lipoprotein cholesterol, hepatic total cholesterol, and hepatic triglycerides were also reduced. ELTA reduced the area under curve (AUC) of blood glucose curves in OGTT and ITT. Relative mRNA level analysis of genes related to MetS showed that ELTA can effectively increase the transcriptional levels of Nrf2, HO-1, PPAR-γ, GluT2, GK, FXR, while effectively decrease those of PTP1B, p65, TNF-α, IL-6, SREBP, 11βHSD-1. Molecular docking showed that the ligands in ELTA can bind to 11βHSD-1, GK, PPAR-γ, and JNK, the important targets involved in MetS.
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2019, Gene
Peroxisome proliferator-activated receptors (PPARs) include the nuclear receptor superfamily of ligand-activated transcription factors involved in several metabolic processes, including carbohydrate and lipid metabolism.
In this study we examined PPARA: rs4253778, rs1800206, PPARD: rs2267668, rs2016520, rs1053049, PPARG rs1801282 and PPARGC1A rs8192678 polymorphisms in patients with unstable angina.
This study included 246 patients with unstable angina confirmed by coronary angiography (defined by >70% stenosis in at least one major coronary artery) and 189 healthy controls.
We observed statistically significant difference in distribution of PPARG rs1801282 genotypes and alleles between patients and control group. Among patients there was the increased frequency of CG and GG genotypes and G alleles. The association between PPARG rs1801282 G allele and unstable angina was confirmed in multivariate regression analysis. There were no statistically significant differences in the distributions of other studied polymorphisms between patients with unstable angina and the control group.
The results of our study suggest the association between PPARG rs1801282 G allele and unstable angina in Polish population.

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Trends in Molecular Medicine

ReviewThe role of PPARs in atherosclerosis

Abstract

Section snippets

PPARs and the recruitment of leukocytes in the early atherosclerotic lesion

PPARs and local immune responses

PPARs, lipid accumulation and reverse cholesterol transport

PPARs and local inflammation

PPARs and fibrous cap development

PPARs and plaque stability

PPARs and thrombosis

PPARs and acute-phase proteins

Anti-atherosclerotic effects of PPARs: results from in vivo studies

Concluding remarks

Acknowledgements

FEBS Lett.

FEBS Lett.

Biochem. Biophys. Res. Commun.

Biochem. Biophys. Res. Commun.

Biochem. Biophys. Res. Commun.

Atherosclerosis

FEBS Lett.

J. Biol. Chem.

Int. Immunopharmacol.

J. Biol. Chem.

Metabolism

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

FEBS Lett.

J. Diabetes Complications

J. Biol. Chem.

J. Biol. Chem.

J. Am. Coll. Cardiol.

Biochem. Biophys. Res. Commun.

Am. J. Pathol.

J. Biol. Chem.

Curr. Biol.

J. Biol. Chem.

Lancet

Blood

J. Biol. Chem.

J. Am. Coll. Cardiol.

Am. J. Cardiol.

J. Diabetes Complications

Atherosclerosis

Nature

Peroxisome proliferator-activated receptors: from transcriptional control to clinical practice

Curr. Opin. Lipidol.

Peroxisome proliferator-activated receptors: nuclear control of metabolism

Endocr. Rev.

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

Proc. Natl. Acad. Sci. U. S. A.

Regulation of lipid and lipoprotein metabolism by PPAR activators

Clin. Chem. Lab. Med.

Peroxisome proliferator-activated receptor γ and metabolic disease

Annu. Rev. Biochem.

Role of peroxisome proliferator-activated receptor α in oxidized phospholipid-induced synthesis of monocyte chemotactic protein-1 and interleukin-8 by endothelial cells

Circ. Res.

Modulation of C-reactive protein-mediated monocyte chemoattractant protein-1 induction in human endothelial cells by anti-atherosclerosis drugs

Circulation

Oxidized LDL reduces monocyte CCR2 expression through pathways involving peroxisome proliferator-activated γ

J. Clin. Invest.

Peroxisome proliferator-activated receptor-γ activators inhibit IFN-γ-induced expression of the T cell-active CXC chemokines IP-10, Mig, and I-TAC in human endothelial cells

J. Immunol.

PPARα activators inhibit cytokine-induced vascular cell adhesion molecule-1 expression in human endothelial cells

Circulation

Peroxisome proliferator-activated receptor activators target human endothelial cells to inhibit leukocyte-endothelial cell interaction

Arterioscler. Thromb. Vasc. Biol.

Modulation of vascular inflammation in vitro and in vivo by peroxisome proliferator-activated receptor-γ activators

Circulation

PPARα and GR differentially down-regulate the expression of nuclear factor-κB-responsive genes in vascular endothelial cells

Endocrinology

Troglitazone inhibits formation of early atherosclerotic lesions in diabetic and nondiabetic low density lipoprotein receptor-deficient mice

Arterioscler. Thromb. Vasc. Biol.

Peroxisome proliferator-activated receptor activators inhibit thrombin-induced endothelin-1 production in human vascular endothelial cells by inhibiting the activator protein-1 signaling pathway

Circ. Res.

Hypertension and insulin resistance: role of peroxisome proliferator-activated receptor γ

Clin. Exp. Pharmacol. Physiol.

Nonhypoglycemic effects of thiazolidinediones

Review
The role of PPARs in atherosclerosis