Bile acids and metabolic surgery

摘要 减肥手术是一种有效的治疗方法，可促进2型糖尿病的持续减肥和缓解。 (T2D)和脂肪肝疾病。尽管减肥手术带来了最显著的新陈代谢改善 在所有可用的肥胖和T2D治疗方法中，它是侵入性的，并且有严重的长期副作用。此外， 低收入人群并不经常接受这种手术，他们受到的影响不成比例。 肥胖和T2D。因此，迫切需要更安全、更负担得起的治疗方法。发展更大的 对减肥手术代谢益处背后的分子机制的理解可能 为开发治疗肥胖、T2D和其他代谢并发症的创新方法提供路线图。 我们的初步数据和在本申请中提出的实验依赖于垂直袖状胃切除术 (VSG)在小鼠中作为模型，以询问减肥手术的分子后果。VSG生产 显著的生理效应，并且通常比其他减肥手术的并发症更少。它 因此成为临床上最受欢迎的减肥手术之一。演出结束后 在肥胖小鼠中，我们观察到血清胆汁酸(BA)成分以及 细胞色素P8B1酶的下调。具体地说，我们观察到12α-羟化(12α-OH)的比率降低 BAs相对于非12α-OHbAs。12个α-OH BA需要细胞色素P8B1在肝脏中合成，并已被 与胰岛素抵抗和非酒精性脂肪性肝病有关。肠道脂肪吸收，这 对体重增加的贡献，在VSG后的小鼠中也大大降低。基于这些令人兴奋的初步 结果：我们假设VSG通过下调细胞色素P8B1而改变肠-肝循环中的特异性bas， 从而限制肠道脂肪的吸收，改变肠道微生物群，从而促进新陈代谢 手术的效果。我们提出了三个具体目标来检验我们的假设：(1)表征 VSG后bas在肠肝循环中的再分布；(2)测定细胞色素P8B1的表达 下调调节介导VSG的代谢效应；以及(3)研究其机制。 细胞色素P8B1的下调参与了VSG的代谢效应。我们将比较VSG对以下方面的影响 野生型，Cyp8b1基因敲除(KO)，CyP8B1过表达，以及Cyp2c70 KO小鼠提供更多 仿人形的BA泳池组成。这些研究将为分子机制提供新的见解。 潜在的减肥手术的有益效果。我们预计我们的发现将导致 开发更安全、非侵入性和更具成本效益的肥胖、T2D和其他代谢疾病的治疗方法 疾病。

ABSTRACT Bariatric surgery is an effective treatment that promotes sustained weight loss and remission of type 2 diabetes (T2D) and fatty liver diseases. Although bariatric surgery produces the most dramatic metabolic improvements of any obesity and T2D treatments available, it is invasive and has severe long-term side effects. Moreover, the surgery is not routinely available to low-income populations, which are disproportionately affected by obesity and T2D. Therefore, safer and more affordable therapies are urgently needed. Developing a greater understanding of the molecular mechanisms that underlie the metabolic benefits of bariatric surgery may provide a roadmap to develop innovative approaches to treat obesity, T2D, and other metabolic complications. Our preliminary data and the experiments proposed in this application rely on vertical sleeve gastrectomy (VSG) in mice as a model to interrogate the molecular consequences of bariatric surgery. VSG produces prominent physiological effects and generally results in fewer complications than other bariatric surgeries. It has thus become one of the most popular bariatric operations performed in clinical practice. After performing VSG in obese mice, we observe dramatic changes in serum bile acid (BA) composition, as well as downregulation of the enzyme CYP8B1. Specifically, we observe reduced ratios of 12α-hydroxylated (12α-OH) BAs relative to non-12α-OH BAs. 12α-OH BAs require CYP8B1 for synthesis in the liver and have been associated with insulin resistance and non-alcoholic fatty liver disease. Intestinal lipid absorption, which contributes to weight gain, is also substantially lower in mice after VSG. Based on these exciting preliminary results, we hypothesize that VSG alters specific BAs in enterohepatic circulation by downregulating CYP8B1, thus restricting intestinal lipid absorption and changing the gut microbiome, which contributes to the metabolic effects of the surgery. We propose three specific aims to test our hypothesis: (1) To characterize the redistribution of BAs along the enterohepatic circuit after VSG; (2) To determine the extent to which CYP8B1 downregulation mediates the metabolic effects of VSG; and (3) To investigate the mechanisms by which CYP8B1 downregulation contributes to the metabolic effects of VSG. We will compare the effects of VSG on wild type, Cyp8b1 knockout (KO), CYP8B1 overexpressing, as well as Cyp2c70 KO mice that confer more human-like BA pool composition. These studies will provide novel insights into the molecular mechanisms underlying the beneficial effects of bariatric surgery. We anticipate that our findings will lead to the development of safer, non-invasive, and more cost-effective therapies for obesity, T2D, and other metabolic diseases.