| First Author | Zhang Y | Year | 2022 |
| Journal | Mol Cell | Volume | 82 |
| Issue | 8 | Pages | 1528-1542.e10 |
| PubMed ID | 35245436 | Mgi Jnum | J:351495 |
| Mgi Id | MGI:7286106 | Doi | 10.1016/j.molcel.2022.01.021 |
| Citation | Zhang Y, et al. (2022) Amelioration of hepatic steatosis by dietary essential amino acid-induced ubiquitination. Mol Cell 82(8):1528-1542.e10 |
| abstractText | 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. |
