"New" hepatic fat activates PPARα to maintain glucose, lipid, and cholesterol homeostasis
"New" hepatic fat activates PPARα to maintain glucose, lipid, and cholesterol homeostasis
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DOI：
10.1016/j.cmet.2005.04.002
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发表时间：
2005-05-01
期刊：
影响因子：
29
通讯作者：
Semenkovich, CF
中科院分区：
文献类型：
--
作者：
Chakravarthy, MV;Pan, ZJ;Semenkovich, CF
从头脂肪生成是一个耗能的过程，其在成年哺乳动物中的作用了解甚少。我们制备了肝脏中脂肪酸合酶（FAS）特异性失活的小鼠，FAS是一种关键的脂肪生成酶。在无脂肪饮食情况下，肝脏中FAS基因敲除（FASKOL）小鼠出现低血糖和脂肪肝，而饮食中添加脂肪可逆转这些情况。在长时间禁食后也观察到这些表型，与禁食的过氧化物酶体增殖物激活受体α（PPARα）缺陷小鼠相似。用PPARα激动剂可纠正FASKOL小鼠的低血糖、脂肪肝以及PPARα靶基因表达的缺陷。在无脂肪饮食或常规饮食情况下，FASKOL小鼠血清和肝脏胆固醇水平较低，同时固醇调节元件结合蛋白 - 2（SREBP - 2）升高，3 - 羟基 - 3 - 甲基戊二酰辅酶A还原酶（HMG - CoA还原酶）表达降低，胆固醇生物合成减少；这些情况也可通过PPARα激动剂纠正。这些结果表明，FAS反应的产物通过作为成年肝脏中不同生理状态下的PPARα的内源性激活剂来调节葡萄糖、脂质和胆固醇代谢。
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.