| First Author | Zhang D | Year | 2024 |
| Journal | Mol Metab | Volume | 85 |
| Pages | 101957 | PubMed ID | 38740087 |
| Mgi Jnum | J:358008 | Mgi Id | MGI:7646392 |
| Doi | 10.1016/j.molmet.2024.101957 | Citation | Zhang D, et al. (2024) Suppression of hepatic ChREBP-CYP2C50 axis-driven fatty acid oxidation sensitizes mice to diet-induced MASLD/MASH. Mol Metab 85:101957 |
| abstractText | 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 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 is both necessary and sufficient to maintain FAO in a cell-autonomous manner independently of its DNA-binding activity. Supplementation of synthetic PPAR/delta agonist is sufficient to restore FAO in Chrebp(-/-) primary mouse hepatocytes. Hepatic ChREBP was decreased in mouse models of diet-induced MAFSLD/MASH and in patients with MASH. Hepatocyte-specific Chrebp knockout impaired FAO, aggravated liver steatosis and inflammation, leading to early-onset fibrosis in response to diet-induced MASH. Conversely, liver overexpression of ChREBP-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 ChREBP. Over-expression of CYP2C50 partially restores hepatic FAO in primary hepatocytes with Chrebp deficiency and attenuates preexisting MASH in the livers of hepatocyte-specific Chrebp-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. |
