Introduction and Objective: Metabolic dysfunction-associated steatohepatitis (MASH), a critical stage in NAFLD progression, lacks effective treatments. While GIP/GLP-1R dual agonists (GIP/GLP-1RA) show therapeutic potential, their mechanisms remain unclear. Our preclinical study identified serum BHMT downregulation by GIP/GLP-1RA. This study investigates the BHMT-incretin relationship, its roles in MASH pathogenesis, and its potential as a therapeutic target for metabolic syndrome.Methods: Serum proteomic analysis was performed in obese diabetic mice following GIP/GLP-1RA treatment. Hepatic fibrosis models were established using a high-fat/high-fructose diet or CCl4 injection in mice with hepatocyte-specific BHMT modulation. BHMT expression was assessed in human and murine MAFLD/MASH livers. Adenovirus, AAV vectors, and recombinant BHMT were used to study cytosolic and secretory BHMT functions in hepatocytes and stellate cells. Systemic and hepatic metabolic phenotypes were evaluated following BHMT manipulation. Proteomics, co-IP, and click chemistry were employed to identify BHMT-interacting proteins and elucidate underlying mechanisms.Results: BHMT is predominantly expressed in hepatocytes. Hepatic BHMT expression progressively decreases during disease progression, while serum BHMT levels slightly increase. Mechanistically, cytoplasmic BHMT interacts with 3-KAT to enhance lipid oxidation, while secreted BHMT is internalized by stellate cells, binding to cleaved NOTCH4 to inhibit the NOTCH4-Hes1 pathway and attenuate fibrosis. Both intrahepatic overexpression and exogenous BHMT supplementation improved metabolic disorders.Conclusion: BHMT functions as a nutrient sensor, in response to GIP/GLP-1-mediated metabolic alterations. Hepatocyte-derived cytosolic and secretory BHMT plays a critical role in liver disease pathogenesis, representing a promising therapeutic target for metabolic syndrome management.
H. Yan: None.
National Natural Science Foundation of China (82300957)
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