Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA, USA; Department of Pediatrics, Juntendo University Faculty of Medicine, Tokyo, Japan.
Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA, USA; Research Services, Central Virginia Veterans Affairs Healthcare System, Richmond, VA, USA.
J Lipid Res. 2023 May;64(5):100363. doi: 10.1016/j.jlr.2023.100363. Epub 2023 Mar 24.
CYP7B1 catalyzes mitochondria-derived cholesterol metabolites such as (25R)26-hydroxycholesterol (26HC) and 3β-hydroxy-5-cholesten-(25R)26-oic acid (3βHCA) and facilitates their conversion to bile acids. Disruption of 26HC/3βHCA metabolism in the absence of CYP7B1 leads to neonatal liver failure. Disrupted 26HC/3βHCA metabolism with reduced hepatic CYP7B1 expression is also found in nonalcoholic steatohepatitis (NASH). The current study aimed to understand the regulatory mechanism of mitochondrial cholesterol metabolites and their contribution to onset of NASH. We used Cyp7b1 mice fed a normal diet (ND), Western diet (WD), or high-cholesterol diet (HCD). Serum and liver cholesterol metabolites as well as hepatic gene expressions were comprehensively analyzed. Interestingly, 26HC/3βHCA levels were maintained at basal levels in ND-fed Cyp7b1 mice livers by the reduced cholesterol transport to mitochondria, and the upregulated glucuronidation and sulfation. However, WD-fed Cyp7b1 mice developed insulin resistance (IR) with subsequent 26HC/3βHCA accumulation due to overwhelmed glucuronidation/sulfation with facilitated mitochondrial cholesterol transport. Meanwhile, Cyp7b1 mice fed an HCD did not develop IR or subsequent evidence of liver toxicity. HCD-fed mice livers revealed marked cholesterol accumulation but no 26HC/3βHCA accumulation. The results suggest 26HC/3βHCA-induced cytotoxicity occurs when increased cholesterol transport into mitochondria is coupled to decreased 26HC/3βHCA metabolism driven with IR. Supportive evidence for cholesterol metabolite-driven hepatotoxicity is provided in a diet-induced nonalcoholic fatty liver mouse model and by human specimen analyses. This study uncovers an insulin-mediated regulatory pathway that drives the formation and accumulation of toxic cholesterol metabolites within the hepatocyte mitochondria, mechanistically connecting IR to cholesterol metabolite-induced hepatocyte toxicity which drives nonalcoholic fatty liver disease.
CYP7B1 催化线粒体衍生的胆固醇代谢物，如 (25R)26-羟基胆固醇 (26HC) 和 3β-羟基-5-胆甾烯-(25R)26-羧酸 (3βHCA)，并促进它们转化为胆汁酸。在没有 CYP7B1 的情况下，26HC/3βHCA 代谢的破坏会导致新生儿肝衰竭。在非酒精性脂肪性肝炎 (NASH) 中也发现了肝 CYP7B1 表达减少导致的 26HC/3βHCA 代谢紊乱。本研究旨在了解线粒体胆固醇代谢物的调节机制及其对 NASH 发病的贡献。我们使用 Cyp7b1 小鼠喂食正常饮食 (ND)、西方饮食 (WD) 或高胆固醇饮食 (HCD)。全面分析血清和肝脏胆固醇代谢物以及肝基因表达。有趣的是，ND 喂养的 Cyp7b1 小鼠肝脏中，由于胆固醇向线粒体的转运减少，以及葡萄糖醛酸化和硫酸化的上调，26HC/3βHCA 水平维持在基础水平。然而，WD 喂养的 Cyp7b1 小鼠发生胰岛素抵抗 (IR)，随后由于葡萄糖醛酸化/硫酸化超负荷和促进的线粒体胆固醇转运，26HC/3βHCA 积累。同时，喂食 HCD 的 Cyp7b1 小鼠不会发生 IR 或随后出现肝毒性的证据。HCD 喂养的小鼠肝脏显示出明显的胆固醇积累，但没有 26HC/3βHCA 积累。结果表明，当增加的胆固醇向线粒体转运与由 IR 驱动的 26HC/3βHCA 代谢减少相结合时，26HC/3βHCA 诱导的细胞毒性就会发生。在饮食诱导的非酒精性脂肪肝小鼠模型和人类标本分析中提供了胆固醇代谢物驱动的肝毒性的支持证据。这项研究揭示了一种胰岛素介导的调节途径，该途径驱动了有毒胆固醇代谢物在肝细胞线粒体中的形成和积累，从机制上连接了 IR 与胆固醇代谢物诱导的肝细胞毒性，从而驱动了非酒精性脂肪性肝病。
