2. Academic Validation
  3. 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

  • Adv Sci (Weinh). 2025 May;12(20):e2410602. doi: 10.1002/advs.202410602.
Senlin Lian 1,  Meixi Lu 2,  Luo Jiajing 2,  Bin Zhang 3,  Yi Fang 3,  Xuran Wang 2,  Minghua Zheng 4,  Yan Ni 5,  Guifang Xu 6,  Yonglin Yang 7,  Runqiu Jiang 1
Affiliations

Affiliations

  • 1 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.
  • 2 Medical School of Nanjing University, Nanjing, Jiangsu Province, 210993, China.
  • 3 Department of Gastroenterology, Affiliated Nanjing Drum Tower Hospital, and Medical School of Nanjing University, Nanjing, Jiangsu Province, 210008, China.
  • 4 NAFLD Research Center, Department of Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, China.
  • 5 The Children's Hospital, National Clinical Research Center for Child Health, Zhejiang University School of Medicine, Hangzhou, 310052, China.
  • 6 Department of Gastroenterology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230022, China.
  • 7 Department of Infectious Diseases, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou, 225300, China.
PMID: 40344326 DOI: 10.1002/advs.202410602
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.

Keywords

Gpbar1; MASH; TRIM21; carnitine; gamma‐butyrobetaine hydroxylase 1; secondary bile acids.

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