DDB1 E3 ligase controls dietary fructose-induced ChREBP? stabilization and liver steatosis via CRY1.

Fructose over-consumption contributes to the development of liver steatosis in part by stimulating ChREBP?-driven de novo lipogenesis. However, the mechanisms by which fructose activates ChREBP pathway remain largely undefined. Here we performed affinity purification of ChREBP? followed by mass spectrometry and identified DDB1 as a novel interaction protein of ChREBP? ...
in the presence of fructose. Depletion and overexpression of Ddb1 showed opposite effects on the ChREBP? 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 Ddb1flox/flox mice showed significantly reduced ChREBP?, lipogenic enzymes, as well as triglycerides in the liver. Mechanistically, DDB1 stabilizes ChREBP? through CRY1, a known ubiquitination target of DDB1 E3 ligase. Finally, overexpression of a degradation-resistant CRY1 mutant (CRY1-585KA) reduces ChREBP? 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 ChREBP? in a CRY1-dependent manner.
Mesh Terms:
Animals, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Cryptochromes, DNA-Binding Proteins, Dietary Carbohydrates, Fatty Liver, Fructose, Hepatocytes, Immediate-Early Proteins, Lipogenesis, Membrane Proteins, Mice, Mice, Inbred C57BL, Mice, Knockout, Mutation, Primary Cell Culture, Ubiquitination
Metabolism
Date: Dec. 01, 2019
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