ORP2 regulates free cholesterol accumulation in hepatocytes during MASH

作者：Jin Wu, Yudi Zhao, Liwen Qiu, Yan Liang, Qiaoli Chen, Xiaowei Wang, Jingwen Gu, Hongyu Wang, Yang Liu, Xiaoqin Wu, Daiwen Chen, Feng‐Jung Chen, Mingming Gao, Hongyuan Yang · 发表于：bioRxiv (Cold Spring Harbor Laboratory) · 年份：2025 · DOI：10.1101/2025.01.03.631227 · 研究领域：Liver Disease Diagnosis and Treatment

Abstract Background Cholesterol crystals in hepatocytes are known to strongly associate with human Metabolic Dysfunction-Associated Steatohepatitis (MASH). However, it remains unclear which molecular pathway(s) regulates free cholesterol accumulation, and therefore 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 internal organelles. 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 wild type 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 ORP2-LKO liver. The expression of Cyp7a1 was significantly upregulated in ORP2-LKO liver, accompanied with accumulation of taurocholic acid. Our results thus unveil an important in vivo function of ORP2 in preventing free cholesterol from accumulating in mouse liver. Conclusions our results suggest that impaired cholesterol trafficking may enhance the deposition of cholesterol crystals in hepatocytes, promoting the development of MASH.