Peroxisome proliferator-activated receptors and cardiovascular remodeling

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that heterodimerize with the retinoid X receptor and then modulate the function of many target genes. Three PPARs are known: alpha, beta/delta, and gamma. The better known are PPAR-alpha and PPAR-gamma, which may be activated by different synthetic agonists, although the endogenous ligands are unknown. PPAR-alpha is involved in fatty acid oxidation and expressed in the liver, kidney, and skeletal muscle, whereas PPAR-gamma is involved in fat cell differentiation, lipid storage, and insulin sensitivity. However, both have been shown to be present in variable amounts in cardiovascular tissues, including endothelium, smooth muscle cells, macrophages, and the heart. The activators of PPAR-alpha (fibrates) and PPAR-gamma (thiazolidinediones or glitazones) antagonized the actions of angiotensin II in vivo and in vitro and exerted cardiovascular antioxidant and anti-inflammatory effects. PPAR activators lowered blood pressure, induced favorable effects on the heart, and corrected vascular structure and endothelial dysfunction in several rodent models of hypertension. Activators of PPARs may become therapeutic agents useful in the prevention of cardiovascular disease beyond their effects on carbohydrate and lipid metabolism. Some side effects, such as weight gain, as well as documented aggravation of advanced heart failure through fluid retention by glitazones, may, however, limit their therapeutic application in prevention of cardiovascular disease.     

Peroxisome proliferator-activated receptors and skin development

PPARs are nuclear hormone receptors. PPAR subtypes (alpha, gamma, delta, the latter a xPPARbeta homologue) were initially investigated in skin because of their known role in regulating lipid metabolism. Studies adding specific PPAR ligand activators to cultured skin or skin cells are compatible with the concepts that PPARalpha activation mediates early lipogenic steps common to the function of both skin epidermal cells (keratinocytes) and sebaceous cells (sebocytes), PPARgamma activation plays a unique role in stimulating sebocyte lipogenesis, and PPARdelta activation may contribute to lipid biosynthesis in both sebocytes and keratinocytes under certain circumstances. Epidermal keratinocytes appear to express small amounts of PPARalpha and PPARdelta mRNA and a trace of PPARgamma mRNA which is up-regulated with differentiation. Sebocytes express all subtypes; PPARgamma gene expression excedes that in epidermis. The emerging data on PPAR protein expression suggests that epidermis normally expresses predominantly PPARalpha, while sebocytes express more PPARgamma than PPARalpha. These expression patterns may change during hyperplasia, differentiation and inflammation. Gene disruption studies in mice are compatible with a contribution of PPARalpha to skin barrier function, suggest that PPARgamma is necessary for sebocyte differentiation, and indicate that PPARdelta can ameliorate inflammatory responses in skin. PPARs appear to play a role in keratinocyte synthesis of the lipids that they export to the intercellular space to form the skin permeability barrier. They also appear to be important for sebocyte formation of the intracellular fused lipid droplets that constitute the holocrine secretion of the sebaceous gland. In addition, they may play roles in keratinocyte growth and differentiation and the inhibition of skin inflammation by diverse mechanisms not necessarily related to fat metabolism.     

Peroxisome proliferator-activated receptor alpha agonist, clofibrate, has profound influence on myocardial fatty acid composition

The hypolipidemic fibrates have been identified as agonists of the peroxisome proliferator-activated receptor alpha (PPARalpha), which plays a critical role in the regulation of cardiac fatty acid metabolism. Despite the widespread clinical use of fibrates, their role in myocardial oxidative stress and fatty acid composition is less known. In this study, male Sprague-Dawley rats were treated with either vehicle (olive oil, 1 ml/kg) or clofibrate (300 mg/kgday i.p.) for 1-14 days. Lipid peroxidation in heart homogenate was determined by thiobarbituric acid reactive substance (TBARS) assay. Results show that hearts from clofibrate-treated rats are more susceptible to FeSO(4)-induced TBARS production. The antioxidants including catalase and glutathione-related enzymes were marginally affected. We demonstrated that myocardial fatty acid composition was dramatically altered by clofibrate treatment. In hearts from clofibrate-treated rats, the principal n-6 polyunsaturated fatty acids (PUFAs), linoleic acid (C18:2 n-6) and arachidonic acid (C20:4 n-6), was significantly reduced, while the content of the principal n-3 PUFA, docosahexaenoic acid (C22:6 n-3), was markedly increased. The overall effect was to reduce n-6/n-3 ratio and increase the unsaturation extent of myocardial fatty acids. Functional study showed that hearts from clofibrate-treated rats had an improved recovery of post-ischemic contractile function and reduced ischemia/reperfusion (I/R)-induced infarct size. The data shows that clofibrate has a profound impact on cardiac fatty acid composition, which may contribute to its cardioprotective effect.     

Peroxisome proliferator-activated receptors modulate proliferation and angiogenesis in human endometrial carcinoma

Peroxisome proliferator-activated receptors (PPAR) and retinoid X receptors (RXR) are implicated in the development of several obesity-related cancers. Little is known of either the expression or function of PPARs and RXRs in endometrial cancer although this increasingly common disease is highly associated with both obesity and insulin resistance. We investigated the expression of PPAR and RXR subtypes in human endometrial cancers and normal endometrium with immunoblotting and immunohistochemistry and subsequently showed PPAR/RXR binding preferences by coimmunoprecipitation. To determine the functions of PPARs within the endometrium, we investigated proliferation, apoptosis, PTEN expression, and secretion of vascular endothelial growth factor (VEGF) in endometrial cell lines after reducing the expression of PPARα and PPARγ with antisense RNA. The functional effects of PPAR ligands were also investigated in vitro. We identified differential expression of PPAR and RXR subtypes in endometrial cancers and discovered that PPARγ expression correlated with expression of PTEN. PPARα activation influences endometrial cell growth and VEGF secretion. PPARγ activation reduces proliferation of endometrial cells via regulation of PTEN and appears to reduce VEGF secretion. We conclude that the PPAR/RXR pathway contribute to endometrial carcinogenesis by control of PTEN expression and modulation of VEGF secretion. We propose that PPAR ligands should be considered for clinical investigation in early phase studies of women with endometrial cancer.     

Peroxisome proliferator-activated receptors alpha and gamma2 polymorphisms in nonalcoholic fatty liver disease: A study in Brazilian patients

Background

Non-alcoholic fatty liver disease (NAFLD) refers to the accumulation of hepatic steatosis in the absence of excess alcohol consumption. The pathogenesis of fatty liver disease and steatohepatitis (NASH) is not fully elucidated, but the common association with visceral obesity, hyperlipidemia, hypertension and type 2 diabetes mellitus (T2DM) suggests that it is the hepatic manifestation of metabolic syndrome. Peroxisome proliferator-activated receptor PPARα and PPARγ are members of a family of nuclear receptors involved in the metabolism of lipids and carbohydrates, adipogenesis and sensitivity to insulin. The objective of this study was to analyze the polymorphisms Leu162Val of PPARα and Pro12Ala of PPARγ as genetic risk factors for the development and progression of NAFLD.

Methods

One hundred and three NAFLD patients (89 NASH, 14 pure steatosis) and 103 healthy volunteers were included. Single nucleotide polymorphisms (SNPs) Leu162Val and Pro12Ala were analyzed by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP).

Results

NASH patients presented higher BMI, AST and prevalence of T2DM than patients with pure steatosis. A higher prevalence of 12Ala allele was observed in the NASH Subgroup when compared to Control Group. When we grouped NASH and Steatosis Subgroups (NAFLD), we found lower serum glucose and more advanced fibrosis in the Leu162Val SNP. On the other hand, there was no statistical difference in clinical, laboratorial and histological parameters according to the Pro12Ala SNP.

Conclusions

We documented a lower prevalence of 12Ala allele of gene PPARγ in the NASH Subgroup when compared to Control Group. In NAFLD patients, there were no associations among the occurrence of Pro12Ala SNP with clinical, laboratorial and histological parameters. We also documented more advanced fibrosis in the Leu162Val SNP. The obtained data suggest that Pro12Ala SNP may result in protection against liver injury and that Leu162Val SNP may be involved in the progression of NAFLD.     

Peroxisome proliferator-activated receptors are expressed in mouse bone marrow-derived mast cells

We examined the expression of peroxisome proliferator-activated receptors (PPARs) and the role of PPARs in cytokine production in mouse bone marrow-derived mast cells (mBMMCs). mBMMCs expressed PPARbeta strongly and gamma slightly, but not alpha. Activation of mBMMCs with antigen or calcium ionophore resulted in the increased expression of PPARgamma mRNA specifically. 15-Deoxy-Delta(12, 14)-prostaglandin J(2) (15d-PGJ(2)) and troglitazone, all PPARgamma ligands, attenuated the antigen-induced cytokine production by mBMMCs. Carbaprostacyclin, a PPARbeta ligand, also inhibited cytokine production, whereas PPARalpha ligands did not. These results suggest that PPARbeta and gamma might be included in the negative regulation of mast cell activation.     

Peroxisome proliferator-activated receptors: three isotypes for a multitude of functions

The peroxisome proliferator-activated receptors (PPARs) are fatty acid and eicosanoid inducible nuclear receptors, which occur in three different isotypes. Upon activator binding, they modulate the expression of various target genes implicated in several important physiological pathways. During the past few years, the identification of both PPAR ligands, natural and synthetic, and PPAR targets and their associated functions has been one of the most important achievements in the field. It underscores the potential therapeutic application of PPAR-specific compounds on the one side, and the crucial biological roles of endogenous PPAR ligands on the other.