2497-P: Hepatocyte METTL2 Deficiency Attenuates MASLD and Insulin Resistance via Suppression of SREBP-1c–Dependent Lipogenesis

Introduction and Objective: Hepatocyte-intrinsic mechanisms linking epitranscriptomic dysregulation to metabolic dysfunction-associated steatotic liver disease (MASLD) remain poorly defined. Our prior work revealed that global METTL2 knockout (KO) mice are resistant to high-fat diet (HFD)-induced obesity and insulin resistance, implicating METTL2 as a metabolic regulator. Here, we sought to define the hepatocyte-specific role of METTL2—a cytoplasmic tRNA m³C methyltransferase—in hepatic steatosis and systemic glucose metabolism. Methods: Alb-Cre-driven hepatocyte-specific METTL2 KO mice were fed either chow or HFD for 20 weeks. For gain-of-function, 8-week-old C57BL/6J mice received AAV8-TBG-METTL2 via tail vein, followed by chow diet for 20 weeks. Metabolic phenotyping (body weight, GTT, ITT), liver histology (H&E, Oil Red O), TG assay, and gene/protein analyses were performed. Results: We observed that hepatic METTL2 expression is enriched under basal conditions but significantly downregulated by HFD, suggesting a potential adaptive response. Hepatocyte-specific METTL2 KO mice resisted HFD-induced obesity, exhibited ameliorated systemic insulin resistance, and showed attenuated hepatic steatosis and inflammation. METTL2 deficiency was associated with decreased SREBP1c protein and downregulation of lipogenic genes (Fasn, Scd1, Cd36). Conversely, hepatic METTL2 overexpression induced spontaneous obesity, glucose intolerance, and hepatic steatosis on chow diet. Conclusion: Hepatocyte-specific METTL2 deficiency ameliorates MASLD and systemic metabolic dysfunction by suppressing SREBP1c-dependent lipogenesis. Targeting METTL2 represents a promising epitranscriptomic strategy for MASLD and associated metabolic disease. Disclosure S. He: None. C. Xu: None. N. Wu: None. L. Lu: None. X. Zhou: None. X. Lin: None. W. Zhang: None. J. Zhou: None. Funding National Natural Science Foundation of China (No. 82270857 and 81870562 to Jiaqiang Zhou)