New hepatic fat activates PPARα to maintain glucose, lipid, and cholesterol homeostasis

被引:429
作者
Chakravarthy, MV
Pan, ZJ
Zhu, YM
Tordjman, K
Schneider, JG
Coleman, T
Turk, J
Semenkovich, CF
机构
[1] Washington Univ, Sch Med, Dept Med, Endocrinol Metab & Lipid Res, St Louis, MO 63110 USA
[2] Washington Univ, Sch Med, Dept Cell Biol & Physiol, St Louis, MO 63110 USA
关键词
D O I
10.1016/j.cmet.2005.04.002
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
De novo lipogenesis is an energy-expensive process whose role in adult mammals is poorly understood. We generated mice with liver-specific inactivation of fatty-acid synthase (FAS), a key lipogenic enzyme. On a zero-fat diet, FASKOL (FAS knockout in liver) mice developed hypoglycemia and fatty liver, which were reversed with dietary fat. These phenotypes were also observed after prolonged fasting, similarly to fasted PPAR alpha-deficiency mice. Hypoglycemia, fatty liver, and defects in expression of PPAR alpha target genes in FASKOL mice were corrected with a PPAR alpha agonist. On either zero-fat or chow diet, FASKOL mice had low serum and hepatic cholesterol levels with elevated SREBP-2, decreased HMG-CoA reductase expression, and decreased cholesterol biosynthesis; these were also corrected with a PPAR alpha agonist. These results suggest that products of the FAS reaction regulate glucose, lipid, and cholesterol metabolism by serving as endogenous activators of distinct physiological pools of PPAR alpha in adult liver.
引用
收藏
页码:309 / 322
页数:14
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