Endocrine Abstracts

Background and aims

Nonalcoholic fatty liver disease (NAFLD) is a major health threat in both developed and developing countries and is a precursor of the more advanced liver diseases including nonalcoholic steatohepatitis (NASH), liver cirrhosis and liver cancer. One of the numerous molecules participating in the development of liver steatosis is p63. Although p63 is mainly known for its roles as a tumor suppressor and cell maintenance and renewal, we have recently reported that it is also relevant in the control of lipid metabolism. More specifically, TAp63α isoform is elevated in the liver of animal models of NAFLD as well as in liver biopsies from obese NAFLD patients. Furthermore, downregulation of p63α in the liver attenuates liver steatosis in diet-induced obese (DIO) mice. Autophagy is a critical intracellular pathway that targets cytoplasmatic components to the lysosome for degradation. A specialized form of autophagy that degrades lipid droplets, is known to be a major pathway of lipid mobilization in hepatocytes. Its impairment has been associated with the development of fatty liver and insulin resistance. Thus, it is established that autophagy acts as a protective mechanism in the pathogenesis of NAFLD. Autophagy-related gene 3 (ATG3) is an enzyme mainly known for its actions in the LC3 lipidation process, which is essential for autophagy. Despite it is implicated in different biological functions, its role in lipid metabolism and its contribution to NAFLD remains unknown.

Results

We found that autophagy-related gene 3 (ATG3) was modified by TAp63α activation and downregulated after p63α inhibition. Further in vitro and in vivo experiments demonstrated that ATG3 is elevated in several animal models of NAFLD and in the liver of patients with NAFLD, who also show a positive correlation between ATG3 and steatosis grade and NAS score. Genetic overexpression of ATG3 increased the lipid load in hepatocytes, while its repression alleviated TAp63α- and diet-induced steatosis. Unexpectedly, ATG3 exerted its role in lipid metabolism by regulating SIRT1 independent of an autophagic action.

Conclusion

Our findings indicate that ATG3 is a novel gene implicated in the development of NAFLD.