Regulation of High-fat Diet-induced Liver Fibrosis by SOCS1 Expression in Hepatic Stellate Cells

Hepatic stellate cells (HSC) are the key mediators of fibrosis development in non-alcoholic fatty liver disease (NAFLD). Hepatic inflammation induced by high-fat diet activates HSCs, which differentiate to myofibroblasts and produce extracellular fibrillar matrix. HSC activation during hepatic fibrogenesis is modulated by cytokines and growth factors produced by stressed hepatocytes and macrophages. SOCS1 is a negative feedback regulator of certain cytokines and growth factors implicated in liver fibrosis.

The goal of this study was to understand the regulatory functions of SOCS1 in HSCs during NAFLD-induced liver fibrosis.

Mice lacking SOCS1 specifically in HSCs (Socs1) and control Socs1-floxed (Socs1) mice were fed choline-deficient L-amino acid-defined high-fat diet (CDA-HFD) or normal control diet for 14 weeks. Body weight gain was regularly monitored. Serum alanine aminotransferase levels and liver weight were assessed at the endpoint. Fibrosis development was evaluated by Sirius red staining and hydroxyproline content, and myofibroblast differentiation by immunohistochemistry. Expression of genes encoding pro-fibrogenic factors, cytokines, growth factors and chemokines, and the phenotype and numbers of intrahepatic leukocytes were evaluated.

Socs1 mice showed increased liver/body weight ratio and displayed increased collagen deposition and myofibroblast differentiation. Induction of Acta2, Col1a1, Pdgfb, IL1b and Ccl2 genes was significantly elevated in Socs1 mice compared to Socs1 controls fed CDA-HFD. Tgfb gene induction was comparable between the two groups, however, Socs1 livers displayed increased SMAD3 phosphorylation. The fibrotic livers of Socs1 mice showed increased inflammatory cell infiltration, and flow cytometry analysis revealed elevated numbers of myeloid cells, granulocytes and myeloid-derived dendritic cells. Socs1 livers harbored increased numbers of Ly6C^hiCCR2+ pro-inflammatory macrophages, largely comprised of Ly6C^hiCCR2+CX3CR1+ cells, suggesting impaired transition to anti-inflammatory macrophages.

Our findings show that SOCS1 exerts non-redundant regulatory functions in HSCs that are critical for attenuating high-fat diet-induced inflammatory response and liver fibrosis development.