Thrap3 promotes nonalcoholic fatty liver disease by suppressing AMPK-mediated autophagy

Abstract

Autophagy functions in cellular quality control and metabolic regulation. Dysregulation of autophagy is one of the major pathogenic factors contributing to the progression of nonalcoholic fatty liver disease (NAFLD). Autophagy is involved in the breakdown of intracellular lipids and the maintenance of healthy mitochondria in NAFLD. However, the mechanisms underlying autophagy dysregulation in NAFLD remain unclear. Here, we demonstrate that the hepatic expression level of Thrap3 was significantly increased in NAFLD conditions. Liver-specific Thrap3 knockout improved lipid accumulation and metabolic properties in a high-fat diet (HFD)-induced NAFLD model. Furthermore, Thrap3 deficiency enhanced autophagy and mitochondrial function. Interestingly, Thrap3 knockout increased the cytosolic translocation of AMPK from the nucleus and enhanced its activation through physical interaction. The translocation of AMPK was regulated by direct binding with AMPK and the C-terminal domain of Thrap3. Our results indicate a role for Thrap3 in NAFLD progression and suggest that Thrap3 is a potential target for NAFLD treatment.

Liver disease: Poor cellular maintenance fuels fatty liverA protein that interferes with a critical cellular housekeeping mechanism offers a promising drug target for non-alcoholic fatty liver disease (NAFLD), a condition that can lead to liver failure. Jang Hyun Choi of the Ulsan National Institute of Science and Technology, South Korea, and colleagues previously demonstrated that a protein called Thrap3 contributes to obesity-related insulin resistance. They have now investigated Thrap3 function in the liver and found that levels were significantly elevated in tissues from NAFLD patients. The researchers demonstrated that they could reduce NAFLD-associated lipid accumulation by using genetic techniques to shut down Thrap3 expression in liver cells. Thrap3 was found to inhibit autophagy, a cellular process for clearing out defective proteins and organelles. Impaired autophagy is a known contributor to NAFLD, and the authors hypothesize that Thrap3 inhibition could protect against this impairment.