MyD88 in hepatic stellate cells promotes the development of alcoholic fatty liver via the AKT pathway

• DOI: 10.1007/s00109-022-02196-1
• Publication Date: 2022-06-16T06:02:36Z
• Authors: Yukun Li; Miaomiao Wei; Qi Yuan; Yu Liu; Tian Tian; Lingling Hou; Jinhua Zhang
• Keywords: Hepatic stellate cell; Lipogenesis; Steatohepatitis; Liver cytology

Abstract Myeloid differentiation primary response gene 88 (MyD88), an adaptor protein in the TLRs signaling pathway, is expressed in various liver cells including hepatocytes, Kupffer cells and hepatic stellate cells (HSCs). However, the specific role of MyD88 in HSCs in alcoholic fatty liver (AFL) has not been well investigated. Here, to study the role of MyD88 in HSCs in the development of AFL and its related molecular mechanism, chronic-binge ethanol mice models were established in mice with specific MyD88 knockout in quiescent (MyD88GFAP−KO) and activated HSCs (MyD88SMA−KO), respectively. The results showed that the expression of MyD88 in HSCs was significantly increased in ethanol-induced liver tissues of wild-type mice. MyD88 deficiency in quiescent HSCs inhibited inflammation and lipogenesis, but in activated HSCs it only inhibited inflammation under the ethanol feeding condition. Further mechanism studies found that MyD88 promoted the osteopontin (OPN) secretion of HSCs, which further activated the AKT signaling pathway of hepatocytes and upregulated lipogenic gene expression to promote fat accumulation. In addition, OPN also promotes inflammation by activating p-STAT1. Thus, MyD88 may represent a potential candidate target for the prevention and targeted therapy in AFL, and MyD88 inhibitor can be also applied in inhibiting adipogenesis.