B4GALT1 deficiency attenuates steatohepatitis by regulating the PPARγ/ACSL4 axis.

Abstract

Lipotoxicity, driven by dysregulated lipid metabolism, is a key initiator of hepatocyte injury in metabolic dysfunction-associated steatotic liver disease (MASLD). β-1,4-galactosyltransferase 1 (B4GALT1), which primarily mediates galactosylation of glycoproteins and glycolipids, is involved in the regulation of plasma lipid composition. Previous studies have implicated aberrant glycosylation in MASLD progression. However, the role and underlying molecular mechanisms of B4GALT1 in MASLD progression remain unclear. The protein levels of B4GALT1 were elevated in patients with MASLD as well as in a murine model of MASLD induced by choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD), with a more pronounced increase observed in MASH. Hepatocyte-specific B4galt1-knockout mice exhibited significantly attenuated hepatic steatosis and inflammation, but not fibrosis. In addition, hepatic B4GALT1 deficiency suppressed the expression of lipogenic genes, reduced lipid accumulation, and inhibited ferroptosis mediated by lipid peroxidation. Mechanistically, B4GALT1 deficiency impaired the N-glycosylation of peroxisome proliferator-activated receptor gamma (PPARγ), leading to its stabilization. Increased PPARγ protein, in turn, transcriptionally repressed acyl-CoA synthetase long chain family member 4 (ACSL4), thereby mitigating lipid peroxidation. Conversely, PPARγ overexpression in steatotic hepatocytes rescued the pro-ferroptotic phenotype driven by B4GALT1. Our findings suggest that B4GALT1 plays a crucial role in MASLD progression by targeting lipid peroxidation in hepatocytes via the PPARγ/ACSL4 axis, thus highlighting a potential therapeutic target for MASLD.