Targeted inhibition of PPARα ameliorates CLA-induced hypercholesterolemia via hepatic cholesterol biosynthesis reprogramming
Targeted inhibition of PPARα ameliorates CLA-induced hypercholesterolemia via hepatic cholesterol biosynthesis reprogramming
复制标题
靶向抑制PPARα通过肝脏胆固醇生物合成重编程改善cla诱导的高胆固醇血症
DOI：
10.1111/liv.15199
复制
发表时间：
2022-02-28
影响因子：
6.7
通讯作者：
Cai, Demin
中科院分区：
文献类型：
--
作者：
Liu, Hao-Yu;Hu, Ping;Cai, Demin
背景与目的：脂质代谢紊乱与代谢紊乱如高胆固醇血症（HCL）和肝脂肪变性密切相关。而胆固醇代谢重编程器可以作为相关干预措施的目标。在这里，我们探讨了饮食共轭亚油酸（CLA）诱导的HCL在小鼠和背后的分子调控。方法：高剂量的CLA补充在饮食中被用来诱导HCL在小鼠中，并被发现会导致一个过度激活的胆固醇生物合成程序在肝脏中，导致胆固醇代谢失调。靶向PPAR α的小分子药物的作用，即，GW 6471在小鼠体内进行了研究，喂养的饮食与CLA补充28天，并在原代肝细胞来源于HCL-mice in vitro.Results：我们证明，CLA诱导HCL和肝脏脂肪变性通过多种途径。其中之一是过氧化物酶体增殖物激活受体α介导的胆固醇生成。发现它通过结合Hmgcr和Dhcr 7（编码胆固醇生物合成途径的关键酶的基因）与SREBP 2合作，并招募组蛋白标记H3 K27 ac和H3 K4 me 1和辅因子。通过阻断PPARalpha和SREBP 2与基因组DNA反应元件的共结合，PPARalpha抑制破坏其与SREBP 2的物理结合。我们发现NR ROR gamma作为一种重要的介体发挥作用，促进了PPAR α和SREBP 2的相互作用，从而调节胆固醇生物合成基因的表达。我们的研究揭示了小分子化合物GW 6471对CLA诱导的HCL发挥了有吸引力的治疗作用，涉及多个途径，其中“PPAR α-ROR γ-SREBP 2”是该肝胆固醇生物合成程序中的潜在复杂参与者。
Background & Aims: 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.Methods: 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 PPAR alpha, 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.Results: We demonstrate that CLA induced HCL and liver steatosis through multiple pathways. Among which was the PPAR alpha-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. PPAR alpha inhibition disrupts its physical association with SREBP2 by blocking cobinding of PPAR alpha and SREBP2 to the genomic DNA response element. We showed that NR ROR gamma functions as an essential mediator that facilitates the interaction of PPAR alpha and SREBP2 to modulate the cholesterol biosynthesis genes expression.Conclusions: Our study unravels that the small-molecule compound GW6471 exerts an attractive therapeutic effect for CLA-induced HCL, involving multiple pathways with the "PPAR alpha-ROR gamma-SREBP2" being a potential complex player in this hepatic cholesterol biosynthesis programming.