Liver specific transgenic expression of CYP7B1 attenuates early Western diet-induced MASLD progression.

Abstract

Effect of liver specific oxysterol 7α-hydroxylase (CYP7B1) overexpression on the Western diet (WD)-induced metabolic dysfunction-associated steatotic liver disease (MASLD) progression was studied in mice. Among various hepatic genes impacted during MASLD development, CYP7B1 is consistently suppressed in multiple MASLD mouse models and in human MASLD cohorts. CYP7B1 enzyme suppression leads to accumulations of bioactive oxysterols such as (25R)26-Hydroxycholesterol (26HC) and 25-hydroxycholesterol (25HC). We challenged liver specific CYP7B1 transgenic (CYP7B1^hep.tg) overexpressing mice with ad libitum WD feeding. Unlike their wild type (WT) counterparts, WD-fed CYP7B1^hep.tg mice developed no significant hepatotoxicity as evidenced by liver histology, lipid quantifications, and serum biomarker analyses. Hepatic 26HC and 25HC levels were maintained at the basal levels. The comparative gene expression/lipidomic analyses between WT and CYP7B1^hep.tg mice revealed that chronically accumulated 26HC initiates LXR/PPAR-mediated hepatic fatty acid uptake and lipogenesis which surpasses fatty acid metabolism and export; compromising metabolic functions. In addition, major pathways related to oxidative stress, inflammation and immune system including retinol metabolism, arachidonic acid metabolism and linoleic acid metabolism were significantly impacted in the WD-fed WT mice. All pathways were unaltered in CYP7B1^hep.tg mice liver. Furthermore, the nucleus of WT mouse liver but not of CYP7B1^hep.tg mouse liver accumulated 26HC and 25HC in response to WD. This data strongly suggested these two oxysterols are specifically important in nuclear transcriptional regulation for the described cytotoxic pathways. In conclusion, this study represents a "proof-of-concept" that maintaining normal mitochondrial cholesterol metabolism with hepatic CYP7B1 expression prevents oxysterol-driven liver toxicity; thus attenuating MASLD progression.