ANGPTL8 accelerates liver fibrosis mediated by HFD-induced inflammatory activity via LILRB2/ERK signaling pathways.

[Display omitted] • The expression level of ANGPTL8 is correlated with liver fibrosis staging. • ANGPTL8 knockout suppresses HFD-induced hepatic steatosis and liver fibrosis in mice. • ANGPTL8 functions as a pro-inflammatory factor induced by HFD, and liver-derived ANGPTL8 interacts with the receptor LILRB2 on the membranes of hepatic stellate cells to activate downstream ERK signaling and increase expression of known liver fibrosis genes. • The serum ANGPTL8 level may represent a potential diagnostic marker for liver fibrosis, and targeting ANGPTL8/LILRB2/ERK signaling holds great promise for developing innovative therapies to treat liver fibrosis. • Metformin can potentially confer protective effects against the pathological progression known to lead to liver fibrosis in vulnerable patient populations. High calorie intake is known to induce nonalcoholic fatty liver disease (NAFLD) by promoting chronic inflammation. However, the mechanisms are poorly understood. This study examined the roles of ANGPTL8 in the regulation of NAFLD-associated liver fibrosis progression induced by high fat diet (HFD)-mediated inflammation. The ANGPTL8 concentration was measured in serum samples from liver cancer and liver cirrhosis patients. ANGPTL8 knockout(KO) mice were used to induce disease models (HFD, HFHC and CCL4) followed by pathological staining, western blot and immunohistochemistry. Hydrodynamic injection of an adeno-associated virus 8 (AAV8) was used to establish a model for restoring ANGPTL8 expression specifically in ANGPTL8 KO mice livers. RNA-sequencing, protein array, Co-IP, etc. were used to study ANGPTL8′s mechanisms in regulating liver fibrosis progression, and drug screening was used to identify an effective inhibitor of ANGPTL8 expression. ANGPTL8 level is associated with liver fibrogenesis in both cirrhosis and hepatocellular carcinoma patients. Mouse studies demonstrated that ANGPTL8 deficiency suppresses HFD-stimulated inflammatory activity, hepatic steatosis and liver fibrosis. The AAV-mediated restoration of liver ANGPTL8 expression indicated that liver-derived ANGPTL8 accelerates HFD-induced liver fibrosis. Liver-derived ANGPTL8, as a proinflammatory factor, activates HSCs (hepatic stellate cells) by interacting with the LILRB2 receptor to induce ERK signaling and increase the expression of genes that promote liver fibrosis. The FDA-approved anti-diabetic drug metformin, an ANGPTL8 inhibitor, inhibited HFD-induced liver fibrosis in vivo. Our data support that ANGPTL8 is a proinflammatory factor that accelerates NAFLD-associated liver fibrosis induced by HFD. The serum ANGPTL8 level may be a potential and specific diagnostic marker for liver fibrosis, and targeting ANGPTL8 holds great promise for developing innovative therapies to treat NAFLD-associated liver fibrosis. [ABSTRACT FROM AUTHOR]