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

Genta Kakiyama ¹, Nanah Bai-Kamara ², Daniel Rodriguez-Agudo ¹

¹Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA, USA; Research Services, Central Virginia Veterans Affairs Health Care System, Richmond, VA, USA.
²Research Services, Central Virginia Veterans Affairs Health Care System, Richmond, VA, USA.
³Junshin Clinic Bile Acid Institute, Meguro-ku, Tokyo, Japan.
⁴Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA, USA; Research Services, Central Virginia Veterans Affairs Health Care System, Richmond, VA, USA; Department of Pediatrics, Juntendo University Faculty of Medicine, Bunkyo-ku, Tokyo, Japan.
⁵Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, MA, USA.
⁶Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond VA, USA.
⁷School of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Ishikari, Hokkaido, Japan.
⁸Department of Pediatrics, Juntendo University Faculty of Medicine, Bunkyo-ku, Tokyo, Japan.
⁹Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA, USA; Stravitz-Sanyal Institute for Liver Disease and Metabolic Health, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.

⁰Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA, USA; Research Services, Central Virginia Veterans Affairs Health Care System, Richmond, VA, USA.

Journal of Lipid Research +

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February 14, 2025

View abstract on PubMed

Summary

Overexpressing liver specific oxysterol 7α-hydroxylase (CYP7B1) in mice prevented Western diet-induced liver toxicity. This highlights CYP7B1’s role in mitigating metabolic dysfunction-associated steatotic liver disease (MASLD) progression by controlling oxysterol accumulation.

Area Of Science

Hepatology
Metabolic Diseases
Molecular Biology

Background

Metabolic dysfunction-associated steatotic liver disease (MASLD) is linked to suppressed hepatic CYP7B1 expression.
CYP7B1 suppression causes accumulation of toxic oxysterols like 26HC and 25HC.
Oxysterol accumulation contributes to liver pathology in MASLD.

Purpose Of The Study

To investigate the protective effect of liver-specific CYP7B1 overexpression against Western diet-induced MASLD.
To elucidate the role of oxysterols in MASLD pathogenesis.

Main Methods

Generation of liver-specific CYP7B1 transgenic mice (CYP7B1<sup>hep.tg</sup>).
Challenging mice with a Western diet (WD).
Analysis of liver histology, lipid profiles, serum biomarkers, gene expression, and oxysterol levels.

Main Results

WD-fed CYP7B1<sup>hep.tg</sup> mice showed no significant hepatotoxicity compared to WT mice.
Hepatic oxysterol levels (26HC, 25HC) were maintained in CYP7B1<sup>hep.tg</sup> mice.
Accumulated oxysterols in WT mice drove lipogenesis, oxidative stress, and inflammation via LXR/PPAR pathways.

Conclusions

Hepatic CYP7B1 overexpression prevents oxysterol accumulation and subsequent liver toxicity.
Maintaining normal cholesterol metabolism via CYP7B1 is a potential therapeutic strategy for MASLD.
Oxysterols play a critical role in nuclear transcriptional regulation of MASLD-related pathways.

Keywords:

CD36 cholesterol inflammation lipotoxicity liver mitochondria oxysterol