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.     

Expression of adiponectin receptors in human macrophages and regulation by agonists of the nuclear receptors PPARalpha, PPARgamma, and LXR

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors expressed in macrophages where they control cholesterol homeostasis and inflammation. In an attempt to identify new PPARalpha and PPARgamma target genes in macrophages, a DNA array-based global gene expression profiling experiment was performed on human primary macrophages treated with specific PPARalpha and PPARgamma agonists. Surprisingly, AdipoR2, one of the two recently identified receptors for adiponectin, an adipocyte-specific secreted hormone with anti-diabetic and anti-atherogenic activities, was found to be induced by both PPARalpha and PPARgamma. AdipoR2 induction by PPARalpha and PPARgamma in primary and THP-1 macrophages was confirmed by Q-PCR analysis. Interestingly, treatment with a synthetic LXR agonist induced the expression of both AdipoR1 and AdipoR2. Furthermore, co-incubation with a PPARalpha ligand and adiponectin resulted in an additive effect on the reduction of macrophage cholesteryl ester content. Finally, AdipoR1 and AdipoR2 are both present in human atherosclerotic lesions. Moreover, AdipoR1 is more abundant than AdipoR2 in monocytes and its expression decreases upon differentiation into macrophages, whereas AdipoR2 remains constant. In conclusion, AdipoR1 and AdipoR2 are expressed in human atherosclerotic lesions and macrophages and can be modulated by PPAR and LXR ligands, thus identifying a mechanism of crosstalk between adiponectin and these nuclear receptor signaling pathways.     

BAG1L enhances trans-activation function of the vitamin D receptor

The vitamin D receptor (VDR) is a member of the steroid/retinoid receptor superfamily of nuclear receptors that has potential tumor-suppressive functions. We show here that VDR interacts with and is regulated by BAG1L, a nuclear protein that binds heat shock 70-kDa (Hsp70) family molecular chaperones. Endogenous BAG1L can be co-immunoprecipitated with VDR from prostate cancer cells (ALVA31; LNCaP) in a ligand-dependent manner. BAG1L, but not shorter non-nuclear isoforms of this protein (BAG1; BAG1M/Rap46), markedly enhanced, in a ligand-dependent manner, the ability of VDR to trans-activate reporter gene plasmids containing a vitamin D response element in transient transfection assays. Mutant BAG1L lacking the C-terminal Hsc70-binding domain suppressed (in a concentration-dependent fashion) VDR-mediated trans-activation of vitamin D response element-containing reporter gene plasmids, without altering levels of VDR or endogenous BAG1L protein, suggesting that it operates as a trans-dominant inhibitor of BAG1L. Gene transfer-mediated elevations in BAG1L protein levels in a prostate cancer cell line (PC3), which is moderately responsive to VDR ligands, increased the ability of natural (1alpha,25(OH)(2) vitamin D(3)) and synthetic (1alpha, 25-dihydroxy-19-nor-22(E)-vitamin D(3)) VDR ligands to induce expression of the VDR target gene, p21(Waf1), and suppress DNA synthesis. Thus, BAG1L is a direct regulator of VDR, which enhances its trans-activation function and improves tumor cell responses to growth-suppressive VDR ligands.     

Effect of vitamin A content in cafeteria diet on the expression of nuclear receptors in rat subcutaneous adipose tissue

The aim of this study was to determine the effects of cafeteria diet containing control or elevated level of vitamin A on the expression of nuclear receptors in adipose tissue. Male Wistar rats were submitted to 3 experimental diets during 8 weeks, a standard diet and two hyper-energetic, hyperlipidic "cafeteria" diets containing normal (Caf) or higher (Caf+) vitamin A level. During the experiment, body weights and energy intakes were measured. At the end of the experimental period, subcutaneous adipose tissue (Swat) and all the fat mass were removed and weighted. Nuclear receptors mRNA levels of RARalpha, RARgamma, RXRalpha, PPARgamma were measured in the Swat by a real-time semi-quantitative RT-PCR method. We observed that energy intake of Caf+ and Caf groups was significantly higher than that of the control group. Despite a higher increase of the energy intake in the Caf group compared to the Caf+ group, no significant difference was observed in the body weight gain of the Caf+ compared to the Caf group. The Caf+ and Caf diets led to a significant increase of adipose tissue in cafeteria groups as observed in the Swat depot. The mRNA levels of PPARgamma and RXRalpha were significantly increased in the Caf+ group as compared to control group, with a significant positive correlation between these two parameters. Expressions of RARalpha and RARgamma were not modified in experimental groups compared to controls. In conclusion, 8-week exposure to cafeteria diets with normal and higher levels of vitamin A led to an increase of adiposity in rats, associated, only in the group fed with the higher vitamin A level cafeteria diet, with an increase of PPARgamma and RXRalpha expressions in subcutaneous adipose tissue.