Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
Laboratory of Aging Biochemistry, College of Life Sciences, Hunan Normal University, Changsha, Hunan, China.
J Gastroenterol Hepatol. 2018 May;33(5):1138-1145. doi: 10.1111/jgh.14046. Epub 2018 Feb 19.
Peroxisome proliferator-activated receptor alpha (PPARα) is a molecular target of various fibrate drugs clinically used to lower serum lipids. However, the tissue-specific functions of PPARα remain to be elucidated. This study aimed to explore the tissue-specific functions of PPARα in response to Wy-14643.
A hepatocyte-specific Ppara knockout mouse line was used to explore the impact of hepatic PPARα activity on the systemic response to treatment with the potent PPARα agonist Wy-14643.
Wy-14643 mainly activated hepatic PPARα and regulated the expression of PPARα target genes in liver. Hepatic Ppara disruption abolished the triglyceride lowering effects of Wy-14643, prevented agonist-induced hypophagia, and ablated PPARα target gene response in the liver.
These findings indicate that Wy-14643 treatment mainly activates hepatic PPARα, and the hypolipidemic and hypophagic effects of Wy-14643 are dependent on PPARα activation within hepatocytes.
过氧化物酶体增殖物激活受体α(PPARα)是各种临床上用于降低血清脂质的贝特类药物的分子靶点。然而,PPARα 的组织特异性功能仍有待阐明。本研究旨在探索 PPARα 在对 Wy-14643 做出反应时的组织特异性功能。
使用肝细胞特异性 Ppara 敲除小鼠系来探讨肝 PPARα 活性对强效 PPARα 激动剂 Wy-14643 全身治疗反应的影响。
Wy-14643 主要激活肝 PPARα,并调节肝脏中 PPARα 靶基因的表达。肝 Ppara 缺失消除了 Wy-14643 的降低甘油三酯作用,阻止了激动剂诱导的食欲减退,并使肝脏中 PPARα 靶基因反应消失。
这些发现表明,Wy-14643 治疗主要激活肝 PPARα,Wy-14643 的降血脂和降低食欲作用依赖于肝细胞内的 PPARα 激活。