CYP8B1 downregulation mediates the metabolic effects of vertical sleeve gastrectomy in mice.

Abstract

BACKGROUND AIMS:

Although the benefits of vertical sleeve gastrectomy surgery (VSG) are well known, the molecular mechanisms by which VSG alleviates obesity and its complications remain unclear. We aim to determine a role of CYP8B1 (cytochrome P450, family 8, subfamily B, polypeptide 1) in mediating the metabolic benefits of VSG.

APPROACH RESULTS:

We found that expression of CYP8B1, a key enzyme in controlling the 12α-hydroxylated (12α-OH) bile acid (BA) to non-12α-OH BA ratio, was strongly downregulated after VSG. Using genetic mouse models of CYP8B1 overexpression, knockdown, and knockout (KO), we demonstrated that overexpression of CYP8B1 dampened the metabolic improvements associated with VSG. In contrast, shRNA mediated CYP8B1 knockdown improved metabolism similar to those observed after VSG. Cyp8b1 deficiency diminished the metabolic effects of VSG. Further, VSG-induced alterations to the 12α-OH/non-12α-OH BA ratio in the BA pool depended on CYP8B1 expression level. Consequently, intestinal lipid absorption was restricted, and the gut microbiota (GM) profile was altered. Fecal microbiota transplantation (FMT) from wild type (WT)-VSG mice (vs. FMT from WT-sham mice) improved metabolism in recipient mice, while there were no differences between mice that received FMT from KO-sham and KO-VSG mice.

CONCLUSIONS:

CYP8B1 is a critical downstream target of VSG. Modulation of BA composition and GM profile by targeting CYP8B1 may provide novel insight into the development of therapies that non-invasively mimic bariatric surgery to treat obesity and its complications.

• Authors: Yanjun Liu, Jui Tu, Linsen Shi, Zhipeng Fang, Mingjie Fan, Jianying Zhang, Lili Ding, Yiqiang Chen, Yangmeng Wang, Eryun Zhang, Senlin Xu, Nisha Sharma, John D Gillece, Lauren J Reining, Lihua Jin, Wendong Huang
• Journal: Hepatology (Baltimore, Md.) (Hepatology) (Oct 11 2023) ISSN: 1527-3350 [Electronic] United States
• PMID: 37820064 (Publication Type: Journal Article)
• Copyright: Copyright © 2023 American Association for the Study of Liver Diseases.