Kersten Sander, Stienstra Rinke
Nutrition, Metabolism and Genomics Group, Division of Human Nutrition, Wageningen University, The Netherlands.
Nutrition, Metabolism and Genomics Group, Division of Human Nutrition, Wageningen University, The Netherlands; Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
Biochimie. 2017 May;136:75-84. doi: 10.1016/j.biochi.2016.12.019. Epub 2017 Jan 8.
The peroxisome proliferator-activated receptor α (PPARα) is a ligand-activated transcription factor that is abundantly expressed in liver. PPARα is activated by fatty acids and various other lipid species, as well as by a class of chemicals referred to as peroxisome proliferators. Studies in mice have shown that PPARα serves as the master regulator of hepatic lipid metabolism during fasting. In addition, PPARα suppresses inflammation and the acute phase response. Comparatively little is known about PPARα in human liver. Here, an overview is provided of the role and regulation of PPARα in human liver. The main outcomes are: 1) the level of PPARA mRNA expression in human and mouse liver is similar. 2) Expression of PPARA in human liver is reduced in patients with non-alcoholic steatohepatitis or infected with the hepatitis C virus. 3) PPARα in human liver is able to effectively induce the expression of numerous genes involved in numerous lipid metabolic pathways, including microsomal, peroxisomal and mitochondrial fatty acid oxidation, fatty acid binding and activation, fatty acid elongation and desaturation, synthesis and breakdown of triglycerides and lipid droplets, lipoprotein metabolism, gluconeogenesis, bile acid metabolism, and various other metabolic pathways and genes. 4) PPARα activation in human liver causes the down-regulation of a large number of genes involved in various immunity-related pathways. 5) Peroxisome proliferators do not promote tumour formation in human liver as opposed to mouse liver because of structural and functional differences between human and mouse PPARα. 6) In addition to helping to correct dyslipidemia, PPARα agonists may hold promise as a therapy for patients with cholestatic liver diseases, non-alcoholic fatty liver disease, and/or type 2 diabetes.
过氧化物酶体增殖物激活受体α（PPARα）是一种配体激活的转录因子，在肝脏中大量表达。PPARα可被脂肪酸和各种其他脂质种类激活，也可被一类称为过氧化物酶体增殖剂的化学物质激活。对小鼠的研究表明，PPARα在禁食期间作为肝脏脂质代谢的主要调节因子。此外，PPARα可抑制炎症和急性期反应。相比之下，人们对人类肝脏中的PPARα了解较少。本文概述了PPARα在人类肝脏中的作用和调节。主要结果如下：1）人类和小鼠肝脏中PPARA mRNA表达水平相似。2）非酒精性脂肪性肝炎患者或感染丙型肝炎病毒的患者肝脏中PPARA的表达降低。3）人类肝脏中的PPARα能够有效诱导许多参与多种脂质代谢途径的基因表达，包括微粒体、过氧化物酶体和线粒体脂肪酸氧化、脂肪酸结合和激活、脂肪酸延长和去饱和、甘油三酯和脂滴的合成与分解、脂蛋白代谢、糖异生、胆汁酸代谢以及各种其他代谢途径和基因。4）人类肝脏中PPARα的激活导致大量参与各种免疫相关途径的基因下调。5）由于人类和小鼠PPARα在结构和功能上的差异，过氧化物酶体增殖剂在人类肝脏中不会像在小鼠肝脏中那样促进肿瘤形成。6）除了有助于纠正血脂异常外，PPARα激动剂有望成为治疗胆汁淤积性肝病、非酒精性脂肪性肝病和/或2型糖尿病患者的一种疗法。
