A gender-related defect in lipid metabolism and glucose homeostasis in peroxisome proliferator-activated receptor α-deficient mice
A gender-related defect in lipid metabolism and glucose homeostasis in peroxisome proliferator-activated receptor α-deficient mice
复制标题
DOI：
10.1172/jci3949
复制
发表时间：
1998-09-15
影响因子：
15.9
通讯作者：
Kelly, DP
中科院分区：
文献类型：
--
作者：
Djouadi, F;Weinheimer, CJ;Kelly, DP
过氧化物酶体增殖体激活受体（PPAR α）是一种参与控制细胞脂质利用的核受体。为了验证PPAR α作为细胞脂质稳态反应的一个组成部分被激活的假设，PPAR α靶基因的表达被表征为对线粒体脂肪酸进口的药物抑制引起的细胞脂质氧化通量扰动的响应。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PPAR α靶基因的反馈诱导。在缺乏PPAR α (PPAR α -/-)的小鼠中，抑制细胞脂肪酸通量导致100%的雄性小鼠大量肝脏和心脏脂质积累、低血糖和死亡，而雌性PPAR α -/-小鼠只有25%。通过2周的β -雌二醇预处理，雄性PPAR α -/-小鼠的代谢表型得以恢复。这些结果表明PPAR α在体内脂质和葡萄糖稳态中起关键作用，并暗示雌激素信号通路参与心脏和肝脏脂质代谢的调节。
The peroxisome proliferator-activated receptor alpha (PPAR alpha) is a nuclear receptor implicated in the control of cellular lipid utilization. To test the hypothesis that PPAR alpha is activated as a component of the cellular lipid homeostatic response, the expression of PPAR alpha 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 PPAR alpha target genes encoding fatty acid oxidation enzymes in liver and heart. In mice lacking PPAR alpha (PPAR alpha-/-), 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 PPAR alpha-/- mice. The metabolic phenotype of male PPAR alpha-/- mice was rescued by a 2-wk pretreatment with beta-estradiol. These results demonstrate a pivotal role for PPAR alpha in lipid and glucose homeostasis in vivo and implicate estrogen signaling pathways in the regulation of cardiac and hepatic lipid metabolism.