Peroxisome Proliferator-Activated Receptor Alpha Target Genes

The peroxisome proliferator-activated receptor alpha (PPARα) is a ligand-activated transcription factor involved in the regulation of a variety of processes, ranging from inflammation and immunity to nutrient metabolism and energy homeostasis. PPARα serves as a molecular target for hypolipidemic fibrates drugs which bind the receptor with high affinity. Furthermore, PPARα binds and is activated by numerous fatty acids and fatty acid-derived compounds. PPARα governs biological processes by altering the expression of a large number of target genes. Accordingly, the specific role of PPARα is directly related to the biological function of its target genes. Here, we present an overview of the involvement of PPARα in lipid metabolism and other pathways through a detailed analysis of the different known or putative PPARα target genes. The emphasis is on gene regulation by PPARα in liver although many of the results likely apply to other organs and tissues as well

Comparative Analysis of Gene Regulation by the Transcription Factor PPARα between Mouse and Human

Studies in mice have shown that PPARalpha is an important regulator of hepatic lipid metabolism and the acute phase response. However, little information is available on the role of PPARalpha in human liver. Here we set out to compare the function of PPARalpha in mouse and human hepatocytes via analysis of target gene regulation

Phyllophaga teosinteophaga (dorsal)

Paratipo hembra de Phyllophaga teosinteophaga Moron y River

Allele compensation in tip60+/- mice rescues white adipose tissue function in vivo.

Adipose tissue is a key regulator of energy homestasis. The amount of adipose tissue is largely determined by adipocyte differentiation (adipogenesis), a process that is regulated by the concerted actions of multiple transcription factors and cofactors. Based on in vitro studies in murine 3T3-L1 preadipocytes and human primary preadipocytes, the transcriptional cofactor and acetyltransferase Tip60 was recently identified as an essential adipogenic factor. We therefore investigated the role of Tip60 on adipocyte differentiation and function, and possible consequences on energy homeostasis, in vivo. Because homozygous inactivation results in early embryonic lethality, Tip60+/- mice were used. Heterozygous inactivation of Tip60 had no effect on body weight, despite slightly higher food intake by Tip60+/- mice. No major effects of heterozygous inactivation of Tip60 were observed on adipose tissue and liver, and Tip60+/- displayed normal glucose tolerance, both on a low fat and a high fat diet. While Tip60 mRNA was reduced to 50% in adipose tissue, the protein levels were unaltered, suggesting compensation by the intact allele. These findings indicate that the in vivo role of Tip60 in adipocyte differentiation and function cannot be properly addressed in Tip60+/- mice, but requires the generation of adipose tissue-specific knock out animals or specific knock-in mice

Comprehensive analysis of PPARα-dependent regulation of hepatic lipid metabolism by expression profiling - 3

PPARα is a ligand-activated transcription factor involved in the regulation of nutrient metabolism and inflammation. Although much is already known about the function of PPARα in hepatic lipid metabolism, many PPARα-dependent pathways and genes have yet to be discovered. In order to obtain an overview of PPARα-regulated genes relevant to lipid metabolism, and to probe for novel candidate PPARα target genes, livers from several animal studies in which PPARα was activated and/or disabled were analyzed by Affymetrix GeneChips. Numerous novel PPARα-regulated genes relevant to lipid metabolism were identified. Out of this set of genes, eight genes were singled out for study of PPARα-dependent regulation in mouse liver and in mouse, rat, and human primary hepatocytes, including thioredoxin interacting protein (Txnip), electron-transferring-flavoprotein β polypeptide (Etfb), electron-transferring-flavoprotein dehydrogenase (Etfdh), phosphatidylcholine transfer protein (Pctp), endothelial lipase (EL, Lipg), adipose triglyceride lipase (Pnpla2), hormone-sensitive lipase (Lipe), and monoglyceride lipase (Mgll). Using an in silico screening approach, one or more PPAR response elements (PPREs) were identified in each of these genes. Since Pnpla2, Lipe, and Mgll contribute to hepatic triglyceride hydrolysis, gene regulation was studied under conditions of elevated hepatic lipids. In wild-type mice fed a high fat diet, the decrease in hepatic lipids following treatment with the PPARα agonist Wy14643 was paralleled by significant up-regulation of Pnpla2, Lipe, and Mgll, suggesting that induction of triglyceride hydrolysis may contribute to the anti-steatotic role of PPARα. Our study illustrates the power of transcriptional profiling to uncover novel PPARα-regulated genes and pathways in liver

Customer segmentation in fashion retailing: a conjoint analysis

PPARα is a ligand-activated transcription factor involved in the regulation of nutrient metabolism and inflammation. Although much is already known about the function of PPARα in hepatic lipid metabolism, many PPARα-dependent pathways and genes have yet to be discovered. In order to obtain an overview of PPARα-regulated genes relevant to lipid metabolism, and to probe for novel candidate PPARα target genes, livers from several animal studies in which PPARα was activated and/or disabled were analyzed by Affymetrix GeneChips. Numerous novel PPARα-regulated genes relevant to lipid metabolism were identified. Out of this set of genes, eight genes were singled out for study of PPARα-dependent regulation in mouse liver and in mouse, rat, and human primary hepatocytes, including thioredoxin interacting protein (Txnip), electron-transferring-flavoprotein β polypeptide (Etfb), electron-transferring-flavoprotein dehydrogenase (Etfdh), phosphatidylcholine transfer protein (Pctp), endothelial lipase (EL, Lipg), adipose triglyceride lipase (Pnpla2), hormone-sensitive lipase (Lipe), and monoglyceride lipase (Mgll). Using an in silico screening approach, one or more PPAR response elements (PPREs) were identified in each of these genes. Since Pnpla2, Lipe, and Mgll contribute to hepatic triglyceride hydrolysis, gene regulation was studied under conditions of elevated hepatic lipids. In wild-type mice fed a high fat diet, the decrease in hepatic lipids following treatment with the PPARα agonist Wy14643 was paralleled by significant up-regulation of Pnpla2, Lipe, and Mgll, suggesting that induction of triglyceride hydrolysis may contribute to the anti-steatotic role of PPARα. Our study illustrates the power of transcriptional profiling to uncover novel PPARα-regulated genes and pathways in liver

Tip60 mRNA, but not protein, is reduced in eWAT of Tip60+/− mice.

<p>A, Tip60 mRNA expression in eWAT of WT and Tip60+/− mice as determined by quantitative RT-PCR (n = 5 per group). Mean expression in WT mice was set at 1. *** p<0.001. B, HEK293T cells were transfected with HA-tagged Tip60 expression construct or empty vector (EV). Cell lysates were subjected to western blot analysis using an anti-HA antibody, a commercial Tip60 antibody (ab #1; sc-5725) or a custom-made Tip60 antibody (ab #2). Tubulin was used as a loading control. C, Tip60 protein expression in eWAT of WT (three individual animals; lanes 1–3) and Tip60+/− mice (lanes 4–6) as determined by Western blotting using 2 different antibodies against Tip60 (ab #1 and ab #2, as in panel B). Tubulin was used as a loading control.</p

Tip60+/− mice display normal eWAT weight and morphology.

<p>A, Epididymal fat pad (eWAT) weights of WT and Tip60+/− mice as percentage of total body weight (BW) on a LFD and HFD regimen, measured after termination. * p<0.05, ** p<0.01. B, Plasma free fatty acid (FFA) levels. * p<0.05. C, H&E staining of representative eWAT sections from WT and Tip60+/− mice after 19 weeks of LFD or HFD feeding. Scale bars indicate 100 µm.</p

Tip60+/− mice display normal liver weight, TG content and morphology.

<p>A, Liver weight as percentage of total body weight (BW) of WT and Tip60+/− mice on a LFD and HFD regimen, measured after termination. * p<0.05, ** p<0.01. B, Liver triglyceride (TG) content. n.s. non-significant. C, H&E staining of representative liver sections of the WT and Tip60+/− mice fed LFD or HFD for 19 weeks. Scale bars indicate 100 µm.</p

Tip60+/− mice display normal bodyweight with higher daily caloric intake.

<p>A, WT and Tip60+/− mice were weighed each week during 19 weeks of LFD or HFD feeding. Error bars represent means ± s.e.m. All groups contained 8 animals, except the Tip60+/− HFD group (n = 6). Please note slight reduction in weight around week 22 due to IP-GTT. B, Daily food intake of WT and Tip60+/− mice on LFD and HFD regimens. ** p<0.01, n.s. non-significant.</p