The METTL2 p.V308L mutation predisposed mice to more severe metabolic impairment, including impaired glucose tolerance and aggravated hepatic steatosis, following a high-fat diet challenge.
The METTL2 p.V308L mutation predisposes mice to impaired metabolic adaptation under high-fat diet stress, highlighting its role in metabolic regulation.
Introduction and Objective: METTL2 is a tRNA methyltransferase involved in the regulation of protein translation. In a previous clinical study, we identified a heterozygous METTL2A mutation (p.V315L) in a family with diabetes and fatty liver disease. This study aimed to investigate the metabolic consequences of this mutation using a point-mutation mouse model. Methods: Pathogenicity of the mutation was predicted in silico (PolyPhen-2/SIFT). A CRISPR/Cas9-generated METTL2 p.V308L knock-in mouse model, corresponding to the human METTL2A p.V315L mutation, underwent metabolic phenotyping under chow and high-fat diet (HFD) conditions. Hematological analysis, gene and protein expression analyses, proteomic analyses, histological evaluation, and computational structural prediction were performed. Results: PolyPhen-2 predicted the METTL2A mutation to be possibly damaging. Under chow diet conditions, no significant metabolic differences were observed between wild-type and mutant mice. Following HFD challenge, mutant mice developed more severe metabolic impairment, characterized by impaired glucose tolerance and aggravated hepatic steatosis. Reduced hepatic CPT1A protein expression was observed in mutant mice, consistent with impaired fatty acid β-oxidation in the context of altered AMPK-ACC-CPT1A signaling. Furthermore, Structural modeling suggested that the p.V315L mutation may alter METTL2A-tRNA interaction dynamics or binding stability. Conclusion: Taken together, these findings indicate that the METTL2 p.V308L mutation predisposes mice to impaired metabolic adaptation under HFD stress, highlighting a role for METTL2 in metabolic regulation. Disclosure C. Xu: None. S. He: None. N. Wu: None. L. Lu: None. X. Lin: None. W. Zhang: None. J. Zhou: None.
XU et al. (Fri,) conducted a other in Metabolic impairment and hepatic steatosis. METTL2 p.V308L mutation vs. Wild-type was evaluated on Metabolic impairment (glucose tolerance and hepatic steatosis). The METTL2 p.V308L mutation predisposed mice to more severe metabolic impairment, including impaired glucose tolerance and aggravated hepatic steatosis, following a high-fat diet challenge.