Bile acids and metabolic surgery

胆汁酸和代谢手术

• 批准号: 10410535
• 负责人: WENDONG HUANG
• 金额: $ 39.6万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-14 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10410535
• 关键词: Affect; Animal Model; Bariatrics; Bile Acid Biosynthesis Pathway; Bile Acids; Blood Circulation; Body Weight decreased; CYP8B1 gene; Data; Dependovirus; Development; Disease remission; Down-Regulation; Enterohepatic Circulation; Enzymes; Face; Frequencies; Gastrectomy; Gene Expression; Generations; Genes; Germ-Free; Goals; Health; Hepatic; Human; Incidence; Insulin Resistance; Intestines; Knock-out; Knockout Mice; Lead; Link; Lipids; Liver; Low Income Population; Measures; Mediating; Metabolic; Metabolic Diseases; Modeling; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Obesity; Operative Surgical Procedures; Physiological; Procedures; Role; Serum; Signal Transduction; Supplementation; Taurocholic Acid; Technology; Testing; Therapeutic; Weight Gain; absorption; bariatric surgery; base; clinical practice; cost; cost effective; cost effective treatment; dietary; effective therapy; experimental study; fatty liver disease; fecal microbiota; glycemic control; gut microbiome; gut microbiota; improved; innovation; insight; microbiota; mouse model; non-alcoholic fatty liver disease; novel; obesity treatment; operation; overexpression; reduce symptoms; sham surgery; side effect; tool

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.

抽象的 减肥手术是一种有效的治疗方法，可促进持续的体重减轻和2型糖尿病的缓解 （T2D）和脂肪肝疾病。尽管减肥手术会产生最大的代谢改善 在任何可用的肥胖和T2D治疗中，它都是侵入性的，具有严重的长期副作用。而且， 该手术通常不适合低收入人群，而这些人群不成比例地受到 肥胖和T2D。因此，迫切需要更安全，更负担得起的疗法。发展更大 了解减肥手术代谢益处的分子机制可能 提供路线图来开发创新的方法来治疗观察，T2D和其他代谢并发症。 我们的初步数据和本应用中提出的实验依赖于垂直套筒胃切除术 （VSG）在小鼠中作为质疑减肥手术的分子后果的模型。 VSG产生 显着的物理作用，通常会导致并发症比其他减肥手术更少。它 因此，已成为临床实践中最受欢迎的减肥手术之一。表演后 VSG在肥胖小鼠中，我们观察到血清胆酸（BA）组成的急剧变化以及 酶CYP8B1的下调。特别是，我们观察到12α-羟基化（12α-OH）的比率降低 BAS相对于非12α-OH BAS。 12α-OH BAS需要CYP8B1在肝脏中合成，并且已经 与胰岛素抵抗和非酒精性脂肪肝疾病有关。肠脂质受苦，这 在VSG之后，小鼠的体重增加也大大降低。基于这些令人兴奋的初步 结果，我们假设VSG通过下调CYP8B1，改变肠球皮循环中的特定BAS， 因此限制了肠道脂质抽象并改变肠道微生物组，这有助于代谢 手术的影响。我们提出了三个特定的目的来检验我们的假设：（1）表征 VSG后沿肠膜片电路的BAS重新分布； （2）确定CYP8B1的程度 下调介导VSG的代谢作用； （3）研究的机制 CYP8B1下调有助于VSG的代谢作用。我们将比较VSG对 野生型，CYP8B1淘汰（KO），CYP8B1过表达，以及CYP2C70 KO小鼠会议更多 类似人类的BA池组成。这些研究将为分子机制提供新的见解 减肥手术的有益作用。我们预计我们的发现将导致 开发肥胖，T2D和其他代谢的更安全，无创和更具成本效益的疗法 疾病。