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

Abstract

BackgroundStudies in mice have shown that PPARα is an important regulator of hepatic lipid metabolism and the acute phase response. However, little information is available on the role of PPARα in human liver. Here we set out to compare the function of PPARα in mouse and human hepatocytes via analysis of target gene regulation.Methodology/Principal FindingsPrimary hepatocytes from 6 human and 6 mouse donors were treated with PPARα agonist Wy14643 and gene expression profiling was performed using Affymetrix GeneChips followed by a systems biology analysis. Baseline PPARα expression was similar in human and mouse hepatocytes. Depending on species and time of exposure, Wy14643 significantly induced the expression of 362–672 genes. Surprisingly minor overlap was observed between the Wy14643-regulated genes from mouse and human, although more substantial overlap was observed at the pathway level. Xenobiotics metabolism and apolipoprotein synthesis were specifically regulated by PPARα in human hepatocytes, whereas glycolysis-gluconeogenesis was regulated specifically in mouse hepatocytes. Most of the genes commonly regulated in mouse and human were involved in lipid metabolism and many represented known PPARα targets, including CPT1A, HMGCS2, FABP1, ACSL1, and ADFP. Several genes were identified that were specifically induced by PPARα in human (MBL2, ALAS1, CYP1A1, TSKU) or mouse (Fbp2, lgals4, Cd36, Ucp2, Pxmp4). Furthermore, several putative novel PPARα targets were identified that were commonly regulated in both species, including CREB3L3, KLF10, KLF11 and MAP3K8.Conclusions/SignificanceOur results suggest that PPARα activation has a major impact on gene regulation in human hepatocytes. Importantly, the role of PPARα as master regulator of hepatic lipid metabolism is generally well-conserved between mouse and human. Overall, however, PPARα regulates a mostly divergent set of genes in mouse and human hepatocytes.

Down-regulation of SREBP-1c is associated with the development of burned-out NASH

“…4B and 7). Consistent with the immunoblot results were no meaningful differences in the mRNA levels of the PPAR target genes CPT1, MCAD, AOX and FABP1 [22][23][24][25], the PPAR/ target genes pyruvate dehydrogenase kinase (PDK) 4 and angiopoietin-like protein 4 (ANGPTL4) [26,27], or the PPAR target genes FABP4 and fat-specific protein 27 (FSP27) [28,29] among the groups ( Fig. 2 and Supplementary Fig.…”

Ginsenoside Rb1 reduces fatty liver by activating AMP-activated protein kinase in obese rats

“…It has subsequently been found to serve as a coactivator of PPAR ␣ and is therefore involved in the transcriptional control of the genes encoding enzymes of fatty acid oxidation ( 29 ). PPAR ␣ , which is highly expressed in the liver, coordinates transcriptional activation of peroxisomal fatty Acox1 ( 30 ) and CPT1A ( 31,32 ). In the current study, Rb1 signifi cantly increased the activity of CPT1 ( Fig.…”

Mulberry leaves (Morus alba L.) ameliorate obesity-induced hepatic lipogenesis, fibrosis, and oxidative stress in high-fat diet-fed mice

“…The current study demonstrated that MLE induced up-regulation of gene expression and/or protein level of PPARa and UCP2 in liver. PPARa and UCP2 are associated with lipid homeostasis and energy expenditure by regulation of energy metabolism and mitochondrial b-oxidation (Rakhshandehroo et al 2009). The results suggest that the MLE administration can alter energy metabolism and mitochondrial b-oxidation of long-chain fatty acids via regulation of PPARa and UCP2.…”