Department of Diabetes Complications and Metabolism, Arthur Riggs Diabetes & Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA.
Research Center of Lipid and Vegetable Protein, School of Food Science and Technology, Jiangnan University, Wuxi, China.
Hepatology. 2024 May 1;79(5):1005-1018. doi: 10.1097/HEP.0000000000000627. Epub 2023 Oct 11.
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.
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.
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.
尽管垂直袖状胃切除术（VSG）的益处众所周知，但 VSG 缓解肥胖及其并发症的分子机制仍不清楚。我们旨在确定 CYP8B1（细胞色素 P450，家族 8，亚家族 B，多肽 1）在介导 VSG 的代谢益处中的作用。
我们发现，控制 12α-羟化（12α-OH）胆汁酸（BA）转化为非 12α-OH BA 比率的关键酶 CYP8B1 的表达在 VSG 后强烈下调。使用 CYP8B1 过表达、敲低和敲除的遗传小鼠模型，我们证明 CYP8B1 的过表达减弱了与 VSG 相关的代谢改善。相比之下，短发夹 RNA 介导的 CYP8B1 敲低改善了类似于 VSG 后观察到的代谢。Cyp8b1 缺乏削弱了 VSG 的代谢作用。此外，VSG 诱导的 BA 库中 12α-OH/非 12α-OH BA 比率的改变依赖于 CYP8B1 的表达水平。因此，肠道脂质吸收受到限制，肠道微生物群（GM）谱发生改变。来自野生型-VSG 小鼠的粪便微生物群移植（与来自野生型-假手术小鼠的粪便微生物群移植相比）改善了受体小鼠的代谢，而来自敲除型-假手术和敲除型-VSG 小鼠的粪便微生物群移植之间没有差异。
CYP8B1 是 VSG 的关键下游靶标。通过靶向 CYP8B1 调节 BA 组成和肠道微生物群谱可能为开发非侵入性模拟减肥手术治疗肥胖及其并发症的疗法提供新的见解。
