氧化还原蛋白2（ORP2）在非酒精性脂肪性肝炎（MASH）期间调节肝细胞中游离胆固醇的积累。
ORP2 regulates free cholesterol accumulation in hepatocytes during MASH.
作者信息
Wu Jin, Zhao Yudi, Qiu Liwen, Chen Qiaoli, Wang Xiaowei, Gu Jingwen, Liang Yan, Zhang Yingjie, Wang Hong-Yu, Liu Yang, Wu Xiaoqin, Chen Shuai, Chen Feng-Jung, Gao Mingming, Yang Hongyuan
机构信息
Shanghai Key Laboratory of Metabolic Remodeling and Health, State Key Laboratory of Genetics and Development of Complex Phenotypes, Institute of Metabolism and Integrative Biology, School of Life Sciences, Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China.
Department of Biochemistry and Molecular Biology, The Key Laboratory of Neural and Vascular Biology, Ministry of Education, The Key Laboratory of Vascular Biology of Hebei Province, Cardiovascular Medical Science Center, Hebei Medical University, Shijiazhuang, Hebei, China.
出版信息
Hepatol Commun. 2025 Jul 14;9(8). doi: 10.1097/HC9.0000000000000737. eCollection 2025 Aug 1.
BACKGROUND
Cholesterol crystals in hepatocytes are known to strongly associate with human metabolic dysfunction-associated steatohepatitis. However, it remains unclear which molecular pathway(s) regulates free cholesterol accumulation and the formation of cholesterol crystals in hepatocytes. In cultured cell lines, oxysterol-binding protein-related protein 2 (ORP2) functions to deliver cholesterol to the plasma membrane from endosomal compartments.
METHODS
Here, we generated liver-specific ORP2 knockout (ORP2-LKO) mice and characterized their metabolic phenotypes on chow and high-fat diet.
RESULTS
The ORP2-LKO mice developed much more severe hepatic steatosis than floxed control mice after high-fat diet feeding. They also demonstrated more severe liver inflammation and damage. Notably, free but not esterified cholesterol, as well as cholesterol crystals, accumulated in the ORP2-LKO liver. The expression of Cyp7a1 was significantly upregulated in the ORP2-LKO liver, accompanied by the accumulation of taurocholic acid. Our results thus unveil an important in vivo function of ORP2 in preventing free cholesterol from accumulating in the mouse liver.
CONCLUSIONS
Our results suggest that impaired cholesterol trafficking may exacerbate the deposition of cholesterol crystals in hepatocytes, promoting the development of metabolic dysfunction-associated steatohepatitis.
背景
已知肝细胞中的胆固醇晶体与人类代谢功能障碍相关脂肪性肝炎密切相关。然而，尚不清楚哪种分子途径调节肝细胞中游离胆固醇的积累和胆固醇晶体的形成。在培养的细胞系中，氧甾醇结合蛋白相关蛋白2（ORP2）的功能是将胆固醇从内体区室转运至质膜。
方法
在此，我们构建了肝脏特异性ORP2基因敲除（ORP2-LKO）小鼠，并对其在正常饮食和高脂饮食条件下的代谢表型进行了表征。
结果
高脂饮食喂养后，ORP2-LKO小鼠发生的肝脂肪变性比对照小鼠严重得多。它们还表现出更严重的肝脏炎症和损伤。值得注意的是，游离而非酯化的胆固醇以及胆固醇晶体在ORP2-LKO小鼠肝脏中积累。Cyp7a1的表达在ORP2-LKO小鼠肝脏中显著上调，同时伴有牛磺胆酸的积累。因此，我们的结果揭示了ORP2在防止游离胆固醇在小鼠肝脏中积累方面的重要体内功能。
结论
我们的结果表明，胆固醇转运受损可能会加剧胆固醇晶体在肝细胞中的沉积，促进代谢功能障碍相关脂肪性肝炎的发展。
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