Inhibiting hepatocytes MAGL alleviates osteoporosis caused by high-fat diet-induced liver fibrosis in male mice.

Abstract

Hepatic osteoporosis is mediated through the liver-bone axis, but the precise mechanisms underlying osteoporosis in severe liver disease remain elusive. A high-fat diet can induce hepatic steatosis, which may subsequently progress to liver fibrosis. Monoacylglycerol lipase (MAGL), a rate-limiting enzyme in monoacylglycerol degradation, exhibits elevated expression in the liver. The potential of hepatic MAGL inhibition to attenuate osteoclast activation and mitigate osteoporosis remains unexplored. This study demonstrated that a high-fat culture medium upregulated MAGL and CB1R expression in mice hepatocytes. Pharmacological inhibition of MAGL using MJN110 resulted in reduced CB1R expression and decreased levels of the apoptosis marker SMAD3, indicating a reduction in liver fibrosis and hepatocyte apoptosis, respectively. Furthermore, we confirmed that CB1R expression decreased in mice hepatocytes with silenced mgll gene expression, mirroring the reduction in MAGL expression. Subsequent stimulation of osteoclasts with concentrated supernatants from hepatocytes cultured in control and mgll-silenced groups revealed a significant reduction in osteoclast activation markers via Western blot and PCR analyses. In vivo, mice fed a high-fat diet to induce liver fibrosis exhibited significant alleviation of liver fibrosis following intraperitoneal injection of MJN110. Notably, osteoclast activation in the femoral germinal layer of mice with liver fibrosis was elevated, whereas this activation was attenuated in the MJN110-treated group. In conclusion, these findings suggest that hepatic MAGL inhibition can alleviate femoral osteoclast activation and bone destruction associated with high-fat diet-induced liver fibrosis, offering a novel therapeutic avenue for hepatic osteoporosis.