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

Deqiang Zhang; Yuee Zhao; Gary Zhang; Daniel Lank; Sarah Cooke; Sujuan Wang; Alli Nuotio-Antar; Xin Tong; Lei Yin

doi:10.1016/j.molmet.2024.101957

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

Mol Metab. 2024 May 11:85:101957. doi: 10.1016/j.molmet.2024.101957. Online ahead of print.

Authors

Deqiang Zhang¹, Yuee Zhao², Gary Zhang¹, Daniel Lank³, Sarah Cooke⁴, Sujuan Wang⁵, Alli Nuotio-Antar⁶, Xin Tong¹, Lei Yin⁷

Affiliations

¹ Department of Molecular & Integrative Physiology, USA; Caswell Diabetes Institute, University of Michigan Medical School, NCRC Building 20-3843, 2800 Plymouth Road, Ann Arbor, MI 48105, USA.
² Department of Molecular & Integrative Physiology, USA; Caswell Diabetes Institute, University of Michigan Medical School, NCRC Building 20-3843, 2800 Plymouth Road, Ann Arbor, MI 48105, USA; Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital, Central South University, 139 Renmin Middle Rd, Furong District, Changsha, Hunan Province 410011, PR China.
³ Department of Pharmacology, University of Virginia, 1340 Jefferson Park Avenue, Charlottesville, VA 22908, USA.
⁴ Neurosciences Graduate Program, Case Western Reserve University School of Medicine, Cleveland, OH 44016, USA.
⁵ Department of Infectious Diseases, The Second Xiangya Hospital, Central South University, 139 Renmin Middle Rd, Furong District, Changsha, Hunan Province 410011, PR China.
⁶ Children Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
⁷ Department of Molecular & Integrative Physiology, USA; Caswell Diabetes Institute, University of Michigan Medical School, NCRC Building 20-3843, 2800 Plymouth Road, Ann Arbor, MI 48105, USA. Electronic address: leiyin@umich.edu.

PMID: 38740087
DOI: 10.1016/j.molmet.2024.101957

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⍺ 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⍺/δ 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.

Keywords: Carbohydrate-response element binding protein (ChREBP); Fatty acid oxidation; Lipid metabolism; Metabolic-Associated Steatohepatitis.