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

Summary

DA-1241 activates GPR119 to drive TFEB nuclear translocation, autophagy, and lysosomal activity, thereby reducing hepatic lipid accumulation in vitro and in high-fat diet-fed mice. Loss of TFEB or GPR119 abolishes the antisteatotic and metabolic benefits, establishing TFEB-mediated autophagy as the mechanism of action.

Key Findings

• DA-1241 induced TFEB nuclear translocation, autophagy, and increased lysosomal activity in hepatocyte models.
• DA-1241 reduced hepatic triglycerides, liver enzymes, and NAFLD activity score in high-fat diet-fed mice, improving glucose tolerance and insulin sensitivity.
• Antisteatotic effects were abolished by GPR119 knockdown and absent in TFEB knockout cells and liver-specific Tfeb knockout mice, demonstrating TFEB dependence.

Clinical Implications

Supports advancing GPR119 agonists toward clinical trials for NAFLD/MASLD in patients with type 2 diabetes, with biomarker strategies leveraging autophagy/TFEB readouts.

Limitations

• Preclinical models only; human pharmacodynamics and safety in NAFLD remain unknown.
• HeLa TFEB knockout and hepatocyte lines may not fully recapitulate human hepatocyte physiology.

Future Directions

First-in-human trials of DA-1241 in NAFLD/MASLD with autophagy/TFEB biomarkers; comparative studies with other autophagy modulators and in NASH-fibrosis models.