Hepatic MED1 disruption ameliorates obesity-related fatty liver by attenuating SREBP1-driven lipogenesis.

BACKGROUND & AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major global health concern, with obesity serving as a primary risk factor. Although Mediator subunit 1 (MED1) plays an important role in lipid metabolism, its specific contribution to obesity-related hepatic steatosis remains unclear. This study aims to elucidate the involvement of MED1 in the pathogenesis of MASLD during obesity. APPROACH & RESULTS: Herein, we found that MED1 expression was upregulated in fatty livers from obese patients with MASLD, a primate MASLD model, genetically obese (ob/ob) mice, and in palmitate-treated HepG2 cells. Hepatocyte-specific knockout of MED1 on an ob/ob background under both chow and high-fat diet feeding ameliorated hepatic steatosis, glucose intolerance, obesity and inflammation of visceral white adipose tissue. Mechanistically, MED1 regulates hepatic lipid metabolism primarily through direct interaction with SREBP1, thereby mediating the expression of key SREBP1 target genes, including ACC, FASN and SCD1. Importantly, therapeutic delivery of AAV8-shMED1 attenuated MASLD progression in ob/ob mice. CONCLUSIONS: These findings establish MED1 as a critical activator of SREBP1-driven lipogenesis and identify hepatic MED1 inhibition as a promising therapeutic strategy for MASLD.