Zhang, Y., Lin, S., Peng, J., Liang, X., Yang, Q., Bai, X., Li, Y., Li, J., Dong, W., Wang, Y., Huang, Y., Pei, Y., Guo, J., Zhao, W., Zhang, Z., Liu, M., Zhu, A.J. (2022). Amelioration of hepatic steatosis by dietary essential amino acid-induced ubiquitination.  Mol. Cell 82(8): 1528--1542.e10.

FBrf0253285

Research paper

Nonalcoholic fatty liver disease (NAFLD) is a global health concern with no approved drugs. High-protein dietary intervention is currently the most effective treatment. However, its underlying mechanism is unknown. Here, using Drosophila oenocytes, the specialized hepatocyte-like cells, we find that dietary essential amino acids ameliorate hepatic steatosis by inducing polyubiquitination of Plin2, a lipid droplet-stabilizing protein. Leucine and isoleucine, two branched-chain essential amino acids, strongly bind to and activate the E3 ubiquitin ligase Ubr1, targeting Plin2 for degradation. We further show that the amino acid-induced Ubr1 activity is necessary to prevent steatosis in mouse livers and cultured human hepatocytes, providing molecular insight into the anti-NAFLD effects of dietary protein/amino acids. Importantly, split-intein-mediated trans-splicing expression of constitutively active UBR2, an Ubr1 family member, significantly ameliorates obesity-induced and high fat diet-induced hepatic steatosis in mice. Together, our results highlight activation of Ubr1 family proteins as a promising strategy in NAFLD treatment.