LIMA1 O‐GlcNAcylation Promotes Hepatic Lipid Deposition through Inducing β‐catenin‐Regulated FASn Expression in Metabolic Dysfunction‐Associated Steatotic Liver Disease

Abstract Hepatic lipid deposition is a key factor in progressing metabolic dysfunction‐associated steatotic liver disease (MASLD). This study investigates the impact of the LIM domain and actin‐binding protein 1 (LIMA1) on hepatic steatotic in MASLD and explore the underlying mechanisms. Increased levels of LIMA1 is observed in both serum and serum sEV of metabolic dysfunction‐associated steatohepatitis (MASH) patients compared to healthy controls, with AUROC values of 0.76 and 0.86, respectively. Furthermore, increased LIMA1 O‐GlcNAcylation is observed in mouse models of MASLD, and steatotic hepatocytes. Mechanistic studies revealed that steatosis upregulated Host cell factor 1 (HCF1) and O‐GlcNAc transferase (OGT) expression, leading to catalyzed O‐GlcNAcylation at the T662 site of LIMA1 and subsequent inhibition of its ubiquitin‐dependent degradation. O‐GlcNAcylation of LIMA1 enhances hepatocyte lipid deposition by activating β‐catenin/FASn‐associated signaling. Additionally, compared with their AAV8‐TBG‐LIMA1‐WT counterparts, AAV8‐TBG‐LIMA1 ΔT662 injection exhibited decreases in systemic insulin resistance, steatosis severity, inflammation and fibrosis in HFD‐fed and CDAHFD‐fed LIMA1 HKO (hepatocyte‐specific knockout) mice. Moreover, LTH‐sEV‐mediated delivery of LIMA1 promoted MASLD progression by promoting hepatic stellate cell (HSC) activation. The findings suggest that serum sEV LIMA1 may be a potential noninvasive biomarker and therapeutic target for individuals with MASH.