Lrg1 inhibits the activation of hepatic macrophages to alleviate NAFLD by enhancing TGF-β1 signaling

Abstract

Background: Non-alcoholic fatty liver disease (NAFLD) is caused by excessive hepatic lipid deposition, and is characterized by hepatocyte steatosis, the accumulation of immune cells and the increased expression of inflammatory factors. Hepatic macrophages are the main hepatic immune cells, which play a decisive role in NAFLD. The inhibition of the M1 polarization of hepatic macrophages or the depletion of hepatic macrophages can alleviate hepatic steatosis and inflammation.Methods and Results: NAFLD mouse model was established by feeding high fat diet (HFD) for 16 weeks, the expression of Lrg1 in liver tissues was detected by Real-time PCR and Western blot. Then expression of Lrg1 in steatotic hepatocytes was detected by Real-time PCR and Western blot. Finally, Western-blot analysis, Real-time PCR, HE staining and immumohistochemical staining were performed to confirm the Lrg1 inhibits the activation of hepatic macrophages to alleviate NAFLD by enhancing TGF-β1 signaling. The results of present study demonstrated that Lrg1 inhibited the polarization of M1 liver macrophages induced by steatotic hepatocyte-derived conditioned medium by enhancing TGF-β1 signaling, and Lrg1 also alleviated liver inflammation induced by a high-fat diet (HFD) via TGF-β1 signaling. In addition, the expression level of Lrg1 was significantly decreased in liver tissues from mice with HFD-induced steatosis. Conclusion: Our findings identify that HFD-induced hepatic expression of Lrg1 was significantly downregulated，Lrg1 inhibits the infiltration of hepatic macrophages to alleviates fatty liver inflammation through enhancing TGF-β1 signaling.