| First Author | Tong X | Year | 2020 |
| Journal | Metabolism | Volume | 107 |
| Pages | 154222 | PubMed ID | 32246987 |
| Mgi Jnum | J:293502 | Mgi Id | MGI:6452898 |
| Doi | 10.1016/j.metabol.2020.154222 | Citation | Tong X, et al. (2020) DDB1 E3 ligase controls dietary fructose-induced ChREBPalpha stabilization and liver steatosis via CRY1. Metabolism 107:154222 |
| abstractText | Fructose over-consumption contributes to the development of liver steatosis in part by stimulating ChREBPalpha-driven de novo lipogenesis. However, the mechanisms by which fructose activates ChREBP pathway remain largely undefined. Here we performed affinity purification of ChREBPalpha followed by mass spectrometry and identified DDB1 as a novel interaction protein of ChREBPalpha in the presence of fructose. Depletion and overexpression of Ddb1 showed opposite effects on the ChREBPalpha stability in hepatocytes. We next tested the impact of hepatic Ddb1 deficiency on the fructose-induced ChREBP pathway. After 3-week high-fructose diet feeding, both Ddb1 liver-specific knockout and AAV-TBG-Cre-injected Ddb1(flox/flox) mice showed significantly reduced ChREBPalpha, lipogenic enzymes, as well as triglycerides in the liver. Mechanistically, DDB1 stabilizes ChREBPalpha through CRY1, a known ubiquitination target of DDB1 E3 ligase. Finally, overexpression of a degradation-resistant CRY1 mutant (CRY1-585KA) reduces ChREBPalpha and its target genes in the mouse liver following high-fructose diet feeding. Our data revealed DDB1 as an intracellular sensor of fructose intake to promote hepatic de novo lipogenesis and liver steatosis by stabilizing ChREBPalpha in a CRY1-dependent manner. |
