Conjugated Lithocholic Acid Activates Hepatic TGR5 to Promote Lipotoxicity and MASLD‐MASH Transition by Disrupting Carnitine Biosynthesis

Conjugated Lithocholic Acid Activates Hepatic TGR5 to Promote Lipotoxicity and MASLD‐MASH Transition by Disrupting Carnitine Biosynthesis

Abstract 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...

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Main Authors: Senlin Lian, Meixi Lu, Luo Jiajing, Bin Zhang, Yi Fang, Xuran Wang, Minghua Zheng, Yan Ni, Guifang Xu, Yonglin Yang, Runqiu Jiang
Format: Article
Language:English
Published: Wiley 2025-05-01
Series:Advanced Science
Subjects:
carnitine
gamma‐butyrobetaine hydroxylase 1
Gpbar1
MASH
secondary bile acids
TRIM21
Online Access:https://doi.org/10.1002/advs.202410602
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Summary:Abstract 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.
ISSN:2198-3844

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