Laminin γ2 accelerates non-alcoholic fatty liver disease progression by enhancing lipid accumulation and fibrogenesis in hepatocytes

Non-alcoholic steatohepatitis (NASH) is characterized by hepatic lipid accumulation and fibrosis, yet the molecular mechanisms linking metabolic dysfunction to extracellular matrix (ECM) remodeling remain poorly defined. This study investigated the role of laminin γ2 (LAMC2, encoded by Lamc2), a basement membrane component, in NASH pathogenesis. Using a high-fat choline-deficient l-amino acid-defined (HF-CDAA) diet-induced murine NASH model and AML12 hepatocytes, we assessed LAMC2 expression via qPCR, immunohistochemistry, and lipidomics. Functional studies included LAMC2 overexpression (adenovirus) and TGFβ pathway inhibition (SB431542). LAMC2 was markedly upregulated in steatotic hepatocytes and localized adjacent to lipid droplets. Laminin-332 (Ln-332), which contains the γ2 chain (LAMC2), directly amplified lipogenesis by increasing Srebf1 and Mlxipl gene expression. TGFβ1 signaling via TGFBR1/Fra2 drove LAMC2 expression. Crucially, LAMC2 amplified both lipogenesis and fibrogenesis, thereby forming a feedforward loop that exacerbated hepatic fibrosis in this predominantly fibrotic NASH model. In vivo, LAMC2 overexpression exacerbated hepatic lipid accumulation and Collagen deposition in the HF-CDAA diet-induced NASH model compared to controls. Fra2 silencing via AAV-shRNA attenuated NASH progression. LAMC2 bridges metabolic and fibrotic reprogramming in NASH through TGFβ1/Fra2-dependent mechanisms. Targeting this ECM-metabolism axis, particularly LAMC2 or Fra2, offers novel therapeutic strategies for fibrosis-dominant NASH, addressing a critical unmet clinical need.

Fibrosis; Hepatocyte; Laminin γ2; NASH; TGFβ1/Fra2 signaling.