ASGR1 Deficiency Promotes Liver Fibrosis by Enhancing Pro-Inflammatory Arachidonic Acid Metabolism and ALP Secretion

Asialoglycoprotein receptor 1 (ASGR1), a hepatocyte-specific receptor, represents a potential therapeutic target for hypercholesterolemia. However, liver safety risks of ASGR1-targeted therapies remain poorly characterized. This study aims to investigate the impact of ASGR1 deficency on liver fibrosis and its underlying mechanisms.

ASGR1 knockout (ASGR1^-/-) mice and wild-type controls were subjected to carbon tetrachloride (CCl₄) administration or bile duct ligation (BDL) to induce liver fibrosis. Serum biomarkers, including alkaline phosphatase (ALP), alanine aminotransferase (ALT), and aspartate aminotransferase (AST), were measured. Transcriptomic analysis was performed to identify altered pathways. Primary mouse hepatocytes, HepG2 cells, and hepatic stellate cells (HSCs) were used for in vitro mechanistic validation.

ASGR1 deficiency significantly exacerbates liver fibrosis in both CCl₄ - and BDL -induced models and specifically induces an increase in serum alkaline phosphatase (ALP), which showed greater sensitivity than alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Mechanistic studies showed that ASGR1 loss led to a significant increase in the transcription and secretion of hepatic ALP. Transcriptomic analysis revealed that ASGR1 knockout mice not only disrupted bile acid metabolism but also upregulated the synthesis of arachidonic acid metabolites (e.g., PTGES, a key enzyme involved in pro-inflammatory eicosanoid synthesis) and the pro-fibrotic factor TGFβ1, collectively accelerating fibrosis. Importantly, Supernatants from ASGR1^-/- primary mouse hepatocytes and HepG2 cells, as well as exogenous ALP, directly activated hepatic stellate cells (HSCs), promoting their activation and α-SMA expression.

ASGR1 deficiency aggravates liver fibrosis, which is likely mediated through the "ASGR1-arachidonic acid-ALP" axis that enhances pro-inflammatory eicosanoid production and ALP secretion. These findings highlight the liver-specific safety risk of ASGR1 as a therapeutic target for lipid disorders and provide mechanistic and translational references for clinical safety monitoring of ASGR1-targeted drugs.