Suppression of hepatic ChREBPâº-CYP2C50 axis-driven fatty acid oxidation sensitizes mice to diet-induced MASLD/MASH.
Mol Metab
; 85: 101957, 2024 Jul.
Article
in En
| MEDLINE
| ID: mdl-38740087
ABSTRACT
OBJECTIVES:
Compromised hepatic fatty acid oxidation (FAO) has been observed in human MASH patients and animal models of MASLD/MASH. It remains poorly understood how and when the hepatic FAO pathway is suppressed during the progression of MASLD towards MASH. Hepatic ChREBP⺠is a classical lipogenic transcription factor that responds to the intake of dietary sugars.METHODS:
We examined its role in regulating hepatocyte fatty acid oxidation (FAO) and the impact of hepatic Chrebpa deficiency on sensitivity to diet-induced MASLD/MASH in mice.RESULTS:
We discovered that hepatocyte ChREBP⺠is both necessary and sufficient to maintain FAO in a cell-autonomous manner independently of its DNA-binding activity. Supplementation of synthetic PPARâº/δ agonist is sufficient to restore FAO in Chrebp-/- primary mouse hepatocytes. Hepatic ChREBP⺠was decreased in mouse models of diet-induced MAFSLD/MASH and in patients with MASH. Hepatocyte-specific Chrebp⺠knockout impaired FAO, aggravated liver steatosis and inflammation, leading to early-onset fibrosis in response to diet-induced MASH. Conversely, liver overexpression of ChREBPâº-WT or its non-lipogenic mutant enhanced FAO, reduced lipid deposition, and alleviated liver injury, inflammation, and fibrosis. RNA-seq analysis identified the CYP450 epoxygenase (CYP2C50) pathway of arachidonic acid metabolism as a novel target of ChREBPâº. Over-expression of CYP2C50 partially restores hepatic FAO in primary hepatocytes with Chrebp⺠deficiency and attenuates preexisting MASH in the livers of hepatocyte-specific Chrebpâº-deleted mice.CONCLUSIONS:
Our findings support the protective role of hepatocyte ChREBPa against diet-induced MASLD/MASH in mouse models in part via promoting CYP2C50-driven FAO.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Oxidation-Reduction
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Hepatocytes
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
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Fatty Acids
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Liver
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Mice, Inbred C57BL
Limits:
Animals
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Female
/
Humans
/
Male
Language:
En
Journal:
Mol Metab
Year:
2024
Document type:
Article
Affiliation country:
United States
Country of publication:
Germany