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Updated: Jul 13, 2025
A Murine Model of Vertical Sleeve Gastrectomy
Published on: December 18, 2017
CYP8B1 downregulation mediates the metabolic effects of vertical sleeve gastrectomy in mice
Yanjun Liu1,2, Jui Tu1,3, Linsen Shi1
1Department of Diabetes Complications and Metabolism, Arthur Riggs Diabetes & Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA.
Background And Aims:
Although the benefits of vertical sleeve gastrectomy (VSG) surgery are well known, the molecular mechanisms by which VSG alleviates obesity and its complications remain unclear. We aim to determine the role of CYP8B1 (cytochrome P450, family 8, subfamily B, polypeptide 1) in mediating the metabolic benefits of VSG.
Approach And 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, we demonstrated that overexpression of CYP8B1 dampened the metabolic improvements associated with VSG. In contrast, short hairpin RNA-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 from wild type-VSG mice (vs. fecal microbiota transplantation from wild-type-sham mice) improved metabolism in recipient mice, while there were no differences between mice that received fecal microbiota transplantation from knockout-sham and knockout-VSG mice.
Conclusions:
CYP8B1 is a critical downstream target of VSG. Modulation of BA composition and gut microbiota profile by targeting CYP8B1 may provide novel insight into the development of therapies that noninvasively mimic bariatric surgery to treat obesity and its complications.
Insights
Vertical sleeve gastrectomy (VSG) downregulates CYP8B1, a key enzyme in bile acid production. Targeting CYP8B1 may offer non-invasive obesity treatments by mimicking VSG's metabolic benefits.
Area of Science:
- Metabolic Surgery
- Molecular Mechanisms
- Obesity Research
Background:
- Vertical sleeve gastrectomy (VSG) offers significant benefits for obesity and related complications.
- The precise molecular pathways underlying VSG's efficacy are not fully understood.
Purpose of the Study:
- To investigate the role of CYP8B1 (cytochrome P450, family 8, subfamily B, polypeptide 1) in mediating the metabolic improvements following VSG.
Main Methods:
- Utilized genetic mouse models with CYP8B1 overexpression, knockdown, and knockout.
- Analyzed changes in bile acid (BA) composition, specifically the 12α-hydroxylated (12α-OH) to non-12α-OH BA ratio.
- Assessed intestinal lipid absorption and gut microbiota (GM) profiles.
- Performed fecal microbiota transplantation (FMT) experiments.
Main Results:
- VSG significantly downregulated CYP8B1 expression.
- CYP8B1 overexpression diminished VSG's metabolic benefits, while knockdown mimicked them.
- CYP8B1 deficiency blunted VSG's effects on metabolism and BA profiles.
- VSG-induced alterations in the 12α-OH/non-12α-OH BA ratio were dependent on CYP8B1 levels.
- Changes in BA composition affected lipid absorption and GM.
- FMT from VSG-treated mice improved recipient metabolism, unlike FMT from CYP8B1 knockout mice.
Conclusions:
- CYP8B1 is a critical downstream target of VSG.
- Modulating BA composition and GM by targeting CYP8B1 offers potential for non-invasive obesity therapies.
- This research provides novel insights into mimicking bariatric surgery effects.
