| RRC ID |
70363
|
| 著者 |
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 AJ.
|
| タイトル |
Amelioration of hepatic steatosis by dietary essential amino acid-induced ubiquitination.
|
| ジャーナル |
Mol Cell
|
| Abstract |
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.
|
| 巻・号 |
82(8)
|
| ページ |
1528-1542.e10
|
| 公開日 |
2022-4-21
|
| DOI |
10.1016/j.molcel.2022.01.021
|
| PII |
S1097-2765(22)00086-7
|
| PMID |
35245436
|
| MeSH |
Amino Acids, Essential / metabolism
Amino Acids, Essential / pharmacology
Amino Acids, Essential / therapeutic use
Animals
Diet, High-Fat / adverse effects
Hepatocytes / metabolism
Liver / metabolism
Mice
Mice, Inbred C57BL
Non-alcoholic Fatty Liver Disease* / genetics
Non-alcoholic Fatty Liver Disease* / prevention & control
Ubiquitination
|
| IF |
15.584
|
| リソース情報 |
| ショウジョウバエ |
HMJ21301
DGRC#115181
DGRC#115301 |
