Hashimoto T, Cook W S, Qi C, Yeldandi A V, Reddy J K, Rao M S
Department of Pathology, Northwestern University Medical School, Chicago, Illinois 60611-3008, USA.
J Biol Chem. 2000 Sep 15;275(37):28918-28. doi: 10.1074/jbc.M910350199.
Fasting causes lipolysis in adipose tissue leading to the release of large quantities of free fatty acids into circulation that reach the liver where they are metabolized to generate ketone bodies to serve as fuels for other tissues. Since fatty acid-metabolizing enzymes in the liver are transcriptionally regulated by peroxisome proliferator-activated receptor alpha (PPARalpha), we investigated the role of PPARalpha in the induction of these enzymes in response to fasting and their relationship to the development of hepatic steatosis in mice deficient in PPARalpha (PPARalpha(-/-)), peroxisomal fatty acyl-CoA oxidase (AOX(-/-)), and in both PPARalpha and AOX (double knock-out (DKO)). Fasting for 48-72 h caused profound impairment of fatty acid oxidation in both PPARalpha(-/-) and DKO mice, and DKO mice revealed a greater degree of hepatic steatosis when compared with PPARalpha(-/-) mice. The absence of PPARalpha in both PPARalpha(-/-) and DKO mice impairs the induction of mitochondrial beta-oxidation in liver following fasting which contributes to hypoketonemia and hepatic steatosis. Pronounced steatosis in DKO mouse livers is due to the added deficiency of peroxisomal beta-oxidation system in these animals due to the absence of AOX. In mice deficient in AOX alone, the sustained hyperactivation of PPARalpha and up-regulation of mitochondrial beta-oxidation and microsomal omega-oxidation systems as well as the regenerative nature of a majority of hepatocytes containing numerous spontaneously proliferated peroxisomes, which appear refractory to store triglycerides, blunt the steatotic response to fasting. Starvation for 72 h caused a decrease in PPARalpha hepatic mRNA levels in wild type mice, with no perceptible compensatory increases in PPARgamma and PPARdelta mRNA levels. PPARgamma and PPARdelta hepatic mRNA levels were lower in fed PPARalpha(-/-) and DKO mice when compared with wild type mice, and fasting caused a slight increase only in PPARgamma levels and a decrease in PPARdelta levels. Fasting did not change the PPAR isoform levels in AOX(-/-) mouse liver. These observations point to the critical importance of PPARalpha in the transcriptional regulatory responses to fasting and in determining the severity of hepatic steatosis.
禁食会导致脂肪组织中的脂肪分解，从而使大量游离脂肪酸释放到循环系统中，这些脂肪酸会到达肝脏，在肝脏中被代谢生成酮体，作为其他组织的燃料。由于肝脏中脂肪酸代谢酶受过氧化物酶体增殖物激活受体α（PPARα）的转录调控，我们研究了PPARα在禁食诱导这些酶过程中的作用，以及它们与PPARα缺陷（PPARα(-/-)）、过氧化物酶体脂肪酰基辅酶A氧化酶（AOX(-/-)）缺陷小鼠以及PPARα和AOX双敲除（DKO）小鼠肝脂肪变性发展的关系。禁食48 - 72小时会导致PPARα(-/-)和DKO小鼠的脂肪酸氧化严重受损，与PPARα(-/-)小鼠相比，DKO小鼠表现出更严重的肝脂肪变性。PPARα(-/-)和DKO小鼠中PPARα的缺失会损害禁食后肝脏中线粒体β氧化的诱导，这会导致低酮血症和肝脂肪变性。DKO小鼠肝脏中明显的脂肪变性是由于这些动物中过氧化物酶体β氧化系统因AOX缺失而额外缺乏。在仅缺乏AOX的小鼠中，PPARα的持续过度激活以及线粒体β氧化和微粒体ω氧化系统的上调，以及大多数含有大量自发增殖过氧化物酶体的肝细胞的再生特性，这些过氧化物酶体似乎难以储存甘油三酯，从而减弱了对禁食的脂肪变性反应。饥饿72小时会导致野生型小鼠肝脏中PPARα mRNA水平下降，PPARγ和PPARδ mRNA水平没有明显的代偿性增加。与野生型小鼠相比，喂食状态下的PPARα(-/-)和DKO小鼠肝脏中PPARγ和PPARδ mRNA水平较低，禁食仅使PPARγ水平略有增加，PPARδ水平下降。禁食并未改变AOX(-/-)小鼠肝脏中PPAR亚型的水平。这些观察结果表明PPARα在对禁食的转录调节反应以及确定肝脂肪变性严重程度方面至关重要。
