Lian Senlin, Lu Meixi, Jiajing Luo, Zhang Bin, Fang Yi, Wang Xuran, Zheng Minghua, Ni Yan, Xu Guifang, Yang Yonglin, Jiang Runqiu
Department of Lab Medicine, The First Affiliated Hospital of Anhui Medical University. MOE Innovation Center for Basic Research in Tumor Immunotherapy, and Anhui Province Key Laboratory of Tumor Immune Microenvironment and Immunotherapy, Hefei, Anhui, 230022, China.
Medical School of Nanjing University, Nanjing, Jiangsu Province, 210993, China.
Adv Sci (Weinh). 2025 May;12(20):e2410602. doi: 10.1002/advs.202410602. Epub 2025 May 8.
Conjugated lithocholic acid (LCA) plays a critical role in the development of metabolic dysfunction-associated steatotic liver disease (MASLD). In this process, hepatocyte inflammation-caused upregulation of its receptor, Takeda G protein-coupled receptor 5 (TGR5) is a crucial factor. Serum bile acid profiling shows an increase in conjugated LCA, which correlates with disease severity. Depletion of Gpbar1 in hepatocytes significantly protects against the progression from MASLD to metabolic dysfunction-associated steatohepatitis (MASH) that is related to conjugated LCA. In vivo and in vitro experiments indicate that TGR5 activation in hepatocytes promotes lipotoxicity-induced cell death and inflammation by suppressing de novo carnitine biosynthesis. Mechanistically, TGR5 binding to CD36 facilitates E3 ubiquitin ligase TRIM21 recruitment, leading to the degradation of BBOX1, a crucial enzyme in de novo carnitine biosynthesis. Targeting TGR5 therapeutically can restore carnitine biosynthesis, which may offer a potent strategy to prevent or reverse the transition from MASLD to MASH.
结合型石胆酸（LCA）在代谢功能障碍相关脂肪性肝病（MASLD）的发展过程中起关键作用。在此过程中，肝细胞炎症导致其受体武田G蛋白偶联受体5（TGR5）上调是一个关键因素。血清胆汁酸谱显示结合型LCA增加，这与疾病严重程度相关。肝细胞中Gpbar1的缺失显著预防了与结合型LCA相关的从MASLD进展为代谢功能障碍相关脂肪性肝炎（MASH）。体内和体外实验表明，肝细胞中TGR5的激活通过抑制从头合成肉碱促进脂毒性诱导的细胞死亡和炎症。从机制上讲，TGR5与CD36结合促进E3泛素连接酶TRIM21的募集，导致BBOX1降解，BBOX1是从头合成肉碱的关键酶。通过治疗靶向TGR5可以恢复肉碱的生物合成，这可能为预防或逆转从MASLD到MASH的转变提供一种有效策略。
