Targeted inhibition of PPARα ameliorates CLA‐induced hypercholesterolemia via hepatic cholesterol biosynthesis reprogramming

脂肪变性 胆固醇7α羟化酶 甾醇调节元件结合蛋白 脂质代谢 胆固醇 过氧化物酶体增殖物激活受体 肝X受体 生物合成 生物 内科学 内分泌学 生物化学 化学 细胞生物学 核受体 甾醇 转录因子 受体 基因 医学
作者
Hao‐Yu Liu,Ping Hu,Yanwei Li,Ming‐an Sun,Huan Qu,Qiufang Zong,Haotian Gu,Xiaobo Chen,Wenbin Bao,Demin Cai
出处
期刊:Liver International [Wiley]
卷期号:42 (6): 1449-1466 被引量:6
标识
DOI:10.1111/liv.15199
摘要

Disruption of lipid metabolism is largely linked to metabolic disorders, such as hypercholesterolemia (HCL) and liver steatosis. While cholesterol metabolic re-programmers can serve as targets for relevant interventions. Here we explored the dietary conjugated linoleic acids (CLA)-induced HCL in mice and the molecular regulation behind it.A high dose of CLA supplementation in the diet was used to induce HCL in mice and was found to cause a hyper-activated cholesterol biosynthesis programme in the liver, leading to cholesterol metabolism dysregulation. The effects of a small-molecule drug targeting PPARα, i.e., GW6471 were studied in vivo in mice fed diets with CLA supplementation for 28 days, and in primary hepatocytes derived from HCL-mice in vitro.We demonstrate that CLA induced HCL and liver steatosis through multiple pathways. Among which was the PPARα-mediated cholesterogenesis. It was found to cooperate with SREBP2 via binding to Hmgcr and Dhcr7 (genes encoding key enzymes of the cholesterol biosynthetic pathway) and recruits the histone marks H3K27ac and H3K4me1 and cofactors. PPARα inhibition disrupts its physical association with SREBP2 by blocking cobinding of PPARα and SREBP2 to the genomic DNA response element. We showed that NR RORγ functions as an essential mediator that facilitates the interaction of PPARα and SREBP2 to modulate the cholesterol biosynthesis genes expression.Our study unravels that the small-molecule compound GW6471 exerts an attractive therapeutic effect for CLA-induced HCL, involving multiple pathways with the "PPARα-RORγ-SREBP2" being a potential complex player in this hepatic cholesterol biosynthesis programming.
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