Bile acids and metabolic surgery

摘要 减肥手术是一种有效的治疗方法，可促进持续减肥和缓解2型糖尿病 (T2D)和脂肪肝。虽然减肥手术能产生最显著的代谢改善 在任何肥胖和T2 D治疗方法中，它是侵入性的，具有严重的长期副作用。此外，委员会认为， 低收入人群不经常接受这种手术， 肥胖和T2 D。因此，迫切需要更安全和更实惠的治疗方法。发展更大的 了解减肥手术代谢益处的分子机制， 为开发治疗肥胖、T2 D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)在小鼠中作为模型来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导致更少的并发症。它 因此成为临床实践中最流行的减肥手术之一。表演后 在肥胖小鼠的VSG中，我们观察到血清胆汁酸（BA）组成的显著变化，以及 酶CYP 8B 1的下调。具体而言，我们观察到12α-羟基化（12α-OH） BA相对于非12α-OH BA。12α-OH BA需要CYP 8B 1在肝脏中合成， 与胰岛素抵抗和非酒精性脂肪肝有关。肠道脂质吸收， 在VSG后小鼠中也显著降低。基于这些令人兴奋的初步 结果，我们假设VSG通过下调CYP 8B 1改变了肝肠循环中的特异性BA， 从而限制肠道脂质吸收并改变肠道微生物组，这有助于代谢 手术的影响。我们提出了三个具体的目标来检验我们的假设：（1）表征 VSG后BA沿着肠肝循环的再分布;（2）确定CYP 8 B1在多大程度上 下调介导VSG的代谢作用;（3）研究VSG的代谢作用机制。 CYP 8B 1下调有助于VSG的代谢作用。我们将比较VSG对 野生型、Cyp 8b 1敲除（KO）、CYP 8B 1过表达以及Cyp 2c 70 KO小鼠， 类人BA库组合物。这些研究将提供新的见解的分子机制 减肥手术的潜在益处。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，T2 D和其他代谢性疾病治疗方法 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.