DA-1241, a GPR119 Agonist, Ameliorates Fatty Liver Through the Upregulation of TFEB-Mediated Autophagy

G protein-coupled receptor 119 (GPR119) is predominantly expressed in pancreatic β-cells, enteroendocrine cells, and the liver. It is a novel therapeutic for dyslipidemia and type 2 diabetes. DA-1241, a GPR119 agonist, improves glucose tolerance by inhibiting gluconeogenesis and enhancing insulin secretion. It mitigates hepatic inflammation by inhibiting NFκB signaling. However, the mechanism by which DA-1241 ameliorates nonalcoholic fatty liver disease (NAFLD) remains unknown. We hypothesized that DA-1241 improves liver steatosis by inducing autophagy in a transcriptional factor EB (TFEB)-dependent manner. It induced autophagy and TFEB nuclear translocation, and decreased lipid content in liver cell lines. Lysotracker staining and DQ-Red BSA assay revealed it increased lysosomal activity. Furthermore, DA-1241 increased the colocalization of mRFP-LC3 and lipid droplets, which were completely abolished by GPR119 knockdown. DA-1241 treatment improved glucose tolerance and insulin sensitivity, reduced liver enzymes activity and hepatic triglyceride levels, and decreased the NAFLD activity score, accompanied by an increased number of autophagosomes and lysosomes in high-fat diet-fed mice. Despite DA-1241 treatment, lysosomal activity and subsequent lipid content reduction were not induced in tfeb knockout HeLa cells. DA-1241 treatment failed to produce favorable metabolic effects, including reduced hepatic triglyceride levels, in liver-specific Tfeb knockout mice. Thus, DA-1241 attenuates hepatic steatosis through TFEB-mediated autophagy induction.

DA-1241 is a novel small-molecule GPR119 agonist. DA-1241 treatment stimulates autophagy induction and transcriptional factor EB (TFEB) nuclear translocation and subsequently reduces hepatic fat accumulation both in vitro and in vivo. DA-1241 treatment increases the lysosomal activity and colocalization of mRFP-LC3 with lipid droplets. The antisteatotic effect of DA-1241 is offset by GPR119 knockdown or in tfeb knockout HeLa cells and liver-specific Tfeb knockout mice.