Djouadi F, Weinheimer C J, Saffitz J E, Pitchford C, Bastin J, Gonzalez F J, Kelly D P
INSERM U319, Université Paris 7, Paris, France.
J Clin Invest. 1998 Sep 15;102(6):1083-91. doi: 10.1172/JCI3949.
The peroxisome proliferator-activated receptor alpha (PPARalpha) is a nuclear receptor implicated in the control of cellular lipid utilization. To test the hypothesis that PPARalpha is activated as a component of the cellular lipid homeostatic response, the expression of PPARalpha target genes was characterized in response to a perturbation in cellular lipid oxidative flux caused by pharmacologic inhibition of mitochondrial fatty acid import. Inhibition of fatty acid oxidative flux caused a feedback induction of PPARalpha target genes encoding fatty acid oxidation enzymes in liver and heart. In mice lacking PPARalpha (PPARalpha-/-), inhibition of cellular fatty acid flux caused massive hepatic and cardiac lipid accumulation, hypoglycemia, and death in 100% of male, but only 25% of female PPARalpha-/- mice. The metabolic phenotype of male PPARalpha-/- mice was rescued by a 2-wk pretreatment with beta-estradiol. These results demonstrate a pivotal role for PPARalpha in lipid and glucose homeostasis in vivo and implicate estrogen signaling pathways in the regulation of cardiac and hepatic lipid metabolism.
过氧化物酶体增殖物激活受体α（PPARα）是一种核受体，参与细胞脂质利用的调控。为了验证PPARα作为细胞脂质稳态反应的一个组成部分被激活这一假说，我们对PPARα靶基因的表达进行了表征，以响应由线粒体脂肪酸导入的药理学抑制所引起的细胞脂质氧化通量的扰动。脂肪酸氧化通量的抑制导致肝脏和心脏中编码脂肪酸氧化酶的PPARα靶基因的反馈诱导。在缺乏PPARα（PPARα-/-）的小鼠中，细胞脂肪酸通量的抑制导致大量肝脏和心脏脂质积累、低血糖，并且100%的雄性PPARα-/-小鼠死亡，但只有25%的雌性PPARα-/-小鼠死亡。雄性PPARα-/-小鼠的代谢表型通过用β-雌二醇进行2周的预处理得以挽救。这些结果证明了PPARα在体内脂质和葡萄糖稳态中的关键作用，并暗示雌激素信号通路参与心脏和肝脏脂质代谢的调节。
