Hebbachi Abdel M, Knight Brian L, Wiggins David, Patel Dilip D, Gibbons Geoffrey F
Metabolic Research Laboratory, Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford OX3 7LJ, UK.
J Biol Chem. 2008 Feb 22;283(8):4866-76. doi: 10.1074/jbc.M709471200. Epub 2007 Dec 13.
The mRNA expression of lipogenic genes Scd-1 and Fas is regulated partly by the insulin-sensitive transcription factor SREBP-1c and liver X receptor alpha (LXRalpha). Compared with normal mice, the increase in the mRNA expression of hepatic Scd-1, Fas, and Srebp-1c was severely attenuated in peroxisome proliferator-activated receptor alpha (PPARalpha)-deficient mice during the transition from the starved to the re-fed states. The concentration of the membrane-bound form of SREBP-1c was also lower in the livers of the PPARalpha-deficient mice during re-feeding but there was little difference in the concentration of the active, nuclear form, or in the abundance of Insig-2a mRNA. The response of plasma insulin to starvation and re-feeding was normal in the PPARalpha-deficient mice. Rat hepatocytes transfected with an adenovirus encoding a dominant negative form of PPARalpha were resistant to the stimulatory effects of insulin on Fas and Scd-1 mRNA expression in vitro. When LXRalpha was activated in vivo by inclusion of a non-steroidal ligand in the diet, the expression of the mRNA for hepatic Srebp-1c, Fas, and Scd-1 was increased severalfold in mice of both genotypes and resistance associated with PPARalpha deficiency was abolished during re-feeding. However, although re-feeding the LXRalpha ligand induced the immature form of SREBP-1c equally in the livers of both genotypes, the concentration of the nuclear form remained relatively low in the livers of the PPARalpha-deficient mice. We conclude that intact PPARalpha is required to mediate the response of Scd-1 and Fas gene expression to insulin and that this is normally achieved directly by activation of LXRalpha.
生脂基因Scd-1和Fas的mRNA表达部分受胰岛素敏感转录因子SREBP-1c和肝X受体α（LXRα）调控。与正常小鼠相比，在从饥饿状态转变为再喂食状态的过程中，过氧化物酶体增殖物激活受体α（PPARα）缺陷小鼠肝脏中Scd-1、Fas和Srebp-1c的mRNA表达增加严重减弱。再喂食期间，PPARα缺陷小鼠肝脏中SREBP-1c的膜结合形式浓度也较低，但活性核形式的浓度或Insig-2a mRNA的丰度几乎没有差异。PPARα缺陷小鼠血浆胰岛素对饥饿和再喂食的反应正常。用编码PPARα显性负性形式的腺病毒转染的大鼠肝细胞在体外对胰岛素对Fas和Scd-1 mRNA表达的刺激作用具有抗性。当通过在饮食中添加非甾体配体在体内激活LXRα时，两种基因型小鼠肝脏中肝Srebp-1c、Fas和Scd-1的mRNA表达均增加数倍，并在再喂食期间消除了与PPARα缺陷相关的抗性。然而, 尽管再喂食LXRα配体在两种基因型小鼠肝脏中均能同等程度地诱导SREBP-1c的未成熟形式，但PPARα缺陷小鼠肝脏中核形式的浓度仍然相对较低。我们得出结论，完整的PPARα是介导Scd-1和Fas基因表达对胰岛素反应所必需的，而这通常是通过直接激活LXRα来实现的。
