Suppression of hepatic ChREBPa-CYP2C50 axis-driven fatty acid oxidation sensitizes mice to diet-induced MASLD/MASH

Authors: ZHANG, DEQIANG - University Of Michigan Medical School; ZHAO, YUEE - University Of Michigan Medical School; ZHANG, GARY - University Of Michigan Medical School; LANK, DANIEL - University Of Virginia; COOKE, SARAH - Case Western Reserve University (CWRU); WANG, SUJUAN - Central South University; NUOTIO-ANTAR, ALLI - Children'S Nutrition Research Center (CNRC); TONG, XIN - University Of Michigan Medical School; YIN, LEI - University Of Michigan Medical School

Submitted to: Molecular Metabolism
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/9/2024
Publication Date: 5/11/2024
Citation: Zhang, D., Zhao, Y., Zhang, G., Lank, D., Cooke, S., Wang, S., Nuotio-Antar, A., Tong, X., Yin, L. 2024. Suppression of hepatic ChREBPa-CYP2C50 axis-driven fatty acid oxidation sensitizes mice to diet-induced MASLD/MASH. Molecular Metabolism. 85. Article 101957. https://doi.org/10.1016/j.molmet.2024.101957.
DOI: https://doi.org/10.1016/j.molmet.2024.101957

Interpretive Summary: Metabolic dysfunction–associated steatotic liver disease (MASLD) is the most common chronic liver disease in the world and is the fastest growing cause of hepatocellular carcinoma. MASLD starts as fatty liver and can progress to its most severe form, metabolic dysfunction-associated steatohepatitis (MASH), which is characterized by increased inflammation and fibrosis in the liver. We wanted to test whether carbohydrate response element binding protein (ChREBP), which regulates sugar metabolism in liver cells, affects the progression of MASLD/MASH. We placed mice that do not have ChREBP in liver cells on a diet that induces MASH and found that lack of ChREBP worsened metabolic processes that were important for protection against MASH. Conversely, we placed mice that have excess ChREBP in liver cells on a diet that induces MASH and found that it improves metabolic processes important for protection against MASH. Further interrogation showed that ChREBP regulates an enzyme important in the metabolism of a fatty acid, and that this was important for the beneficial effects of ChREBP against MASH. Taken together, our data provide a new target for the prevention and treatment of MASH.

Technical Abstract: 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 ChREBPa is a classical lipogenic transcription factor that responds to the intake of dietary sugars. 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. We discovered that hepatocyte ChREBPa is both necessary and sufficient to maintain FAO in a cell-autonomous manner independently of its DNA-binding activity. Supplementation of synthetic PPARa/B agonist is sufficient to restore FAO in Chrebp-/- primary murine hepatocytes. Hepatic ChREBPa was decreased in mouse models of diet-induced MAFSLD/MASH and in patients with MASH. Hepatocyte-specific Chrebpa knockout impaired FAO, aggravated liver steatosis and inflammation, leading to early-onset fibrosis in response to diet-induced MASH. Conversely, liver overexpression of ChREBPa-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 ChREBPa. Over-expression of CYP2C50 partially restores hepatic FAO in primary hepatocytes with Chrebpa deficiency and attenuates preexisting MASH in the livers of hepatocyte-specific Chrebpa-deleted mice. Thus, our findings support the protective role of hepatocyte ChREBPa against diet-induced MASLD/MASH in mouse models in part via promoting CYP2C50-driven FAO.