Adipokine gremlin‐1 promotes hepatic steatosis via upregulation of ER stress by suppressing autophagy‐mediated signaling

Gremlin-1 (GR1) is a novel adipokine that is highly expressed in human adipocytes and has been shown to inhibit the BMP2/4-TGFb signaling pathway. It has an effect on insulin sensitivity. Elevated levels of Gremlin have been shown to lead to insulin resistance in skeletal muscle, adipocytes, and hepatocytes. In this study, we investigated the effect of GR1 on hepatic lipid metabolism under hyperlipidemic conditions and explored the molecular mechanisms associated with GR1 by in vitro and in vivo studies. We found that palmitate increased GR1 expression in visceral adipocytes. Recombinant GR1 increased lipid accumulation, lipogenesis, and ER stress markers in cultured primary hepatocytes. Treatment with GR1 increased EGFR expression and mTOR phosphorylation and reduced autophagy markers. EGFR or rapamycin siRNA reduced the effects of GR1 on lipogenic lipid deposition and ER stress in cultured hepatocytes. Administration of GR1 via the tail vein induced lipogenic proteins and ER stress while suppressing autophagy in the livers of experimental mice. Suppression of GR1 by in vivo transfection reduced the effects of a high-fat diet on hepatic lipid metabolism, ER stress, and autophagy in mice. These results suggest that the adipokine GR1 promotes hepatic ER stress due to the impairment of autophagy, ultimately causing hepatic steatosis in the obese state. The current study demonstrated that targeting GR1 may be a potential therapeutic approach for treating metabolic diseases, including metabolic-associated fatty liver disease (MAFLD).