Department of Food Science, Aarhus University, Denmark.
Department of Biology, Copenhagen University, Denmark.
Biochem Pharmacol. 2020 Feb;172:113736. doi: 10.1016/j.bcp.2019.113736. Epub 2019 Nov 29.
Fasting has been shown to regulate the expression of the cytochrome p450 (CYP) enzyme system in the liver. However, the exact mechanism behind the fasting-induced regulation of the CYP's remains unknown. In the present study we tested the hypothesis that the peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α), which is a key-regulator of energy metabolism, is responsible for the fasting-induced regulation of the CYP's. Lox/lox and liver specific PGC-1α (LKO) mice of both sexes, fasted for 18 h and the content of the CYP's as well as the hepatic metabolome was assessed. Fasting increased the mRNA content of Cyp2a4, Cyp2e1, Cyp3a11 and Cyp4a10. The fasting-induced response in Cyp4a10 mRNA content was different between lox/lox and LKO mice, while the absence of PGC-1α had no effect on the fasting-induced response for the other Cyp's. Moreover, the fasting-induced response in mRNA content of Sirtinus 1 and Perilipin 2 was different between lox/lox and LKO mice. Only the CYP1A isoform showed a fasting-induced response at the protein level. Absence of hepatic PGC-1α had no effect on the apparent metabolome, where fasting vs fed was the only discriminate in the following multivariate analysis. In conclusion, hepatic PGC-1α is not essential for the fasting-induced regulation of hepatic CYP's.
禁食已被证明可调节肝脏细胞色素 P450（CYP）酶系统的表达。然而，禁食诱导 CYP 调节的确切机制尚不清楚。在本研究中，我们检验了这样一个假设，即过氧化物酶体增殖物激活受体γ共激活因子 1α（PGC-1α），作为能量代谢的关键调节剂，负责禁食诱导的 CYP 调节。雌雄两性lox/lox 和肝特异性 PGC-1α（LKO）小鼠禁食 18 小时，评估 CYP 的含量和肝代谢组。禁食增加了 Cyp2a4、Cyp2e1、Cyp3a11 和 Cyp4a10 的 mRNA 含量。lox/lox 和 LKO 小鼠之间 Cyp4a10 mRNA 含量的禁食诱导反应不同，而 PGC-1α 的缺失对其他 Cyp 的禁食诱导反应没有影响。此外，lox/lox 和 LKO 小鼠之间 Sirtinus 1 和 Perilipin 2 的 mRNA 含量的禁食诱导反应也不同。只有 CYP1A 同工型在蛋白质水平上显示出禁食诱导反应。肝 PGC-1α 的缺失对明显的代谢组没有影响，禁食与喂养是以下多元分析中唯一的区别。总之，肝 PGC-1α 对于肝 CYP 的禁食诱导调节不是必需的。
