NAFLD Improvement after Bariatric Surgery: The role of bile acid signaling

减肥手术后 NAFLD 的改善：胆汁酸信号传导的作用

• 批准号: 9462799
• 负责人: Rohit Kohli
• 金额: $ 48.21万
• 依托单位: CHILDREN'S HOSPITAL OF LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9462799
• 关键词: Abdomen; Acids; Adolescent; Adolescent obesity; Adult; Adverse effects; Affect; Agonist; Bariatrics; Bile Acids; Bile fluid; Body Weight decreased; Calories; Cell Culture Techniques; Cells; Cirrhosis; Clinical Trials; Comorbidity; Data; Development; Eating; Elements; Enterocytes; FGF19 gene; FGFR4 gene; Fatty Liver; Fatty acid glycerol esters; Fibroblast Growth Factor; Funding; Gastrectomy; Gastric Bypass; Genes; Goals; Hepatic; Hepatocyte; Histologic; Human; Hyperlipidemia; In Vitro; Injury; Intake; Intestines; Link; Lipids; Liver; Liver diseases; Malabsorption Syndromes; Mediating; Messenger RNA; Metabolic; Molecular; Morbid Obesity; Mus; Nature; Nuclear Receptors; Obesity; Obesity associated liver disease; Operative Surgical Procedures; Orthologous Gene; Outcome; Pancreas; Phase III Clinical Trials; Play; Populations at Risk; Procedures; Proteins; Rattus; Reporting; Resolution; Risk; Rodent; Role; Serum; Signal Pathway; Signal Transduction; Site; Small Interfering RNA; Stomach; System; Technology; Testing; Tissues; Triglycerides; United States; United States National Institutes of Health; Weight; Work; bariatric surgery; base; cost; food restriction; glucose production; ileum; improved; in vivo; lifestyle intervention; liver transplantation; mimetics; mouse model; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; public health relevance; receptor; relating to nervous system; success

?DESCRIPTION (provided by applicant): Bariatric surgery remains the most effective and durable treatment option for obesity to date. More importantly, beyond weight loss, bariatric procedures have many advantageous metabolic effects including resolution of advanced obesity related liver disease or nonalcoholic steatohepatitis (NASH). Steatosis (fat in liver cells) is the defining element of NASH and a precursor to the development of cirrhosis and the potential need for liver transplantation. In particular, we have studied the potent impact of a bariatric procedure termed Vertical Sleeve Gastrectomy (VSG) on resolution of NASH. Simultaneously we have observed increased serum bile acids and downstream bile acid signaling in mice that undergo VSG surgery. Importantly, these effects are not simply the result of weight loss since our data show that the resolution of NASH and increase in serum bile acids are not seen in rodents that lose an equivalent amount of weight via food restriction. These studies build on our prior work wherein we have studied other bariatric procedures and their effects on bile acid driven signaling. These have included experimental procedures such as "ileal transposition" or bile diversion and established procedures such as roux-en Y gastric bypass and the adjustable gastric band. In this proposal Dr. Kohli will focus on the mechanisms of NASH resolution after VSG surgery using an obese murine model. The specific aims of his proposal will examine the effect of a specific bile acid triggered intestinal signal, fibroblast growth factor 15/19 (Fgf15/1). In inter-related aims Dr. Kohli proposes to study the mechanism of (Aim 1) intestinal; and (Aim 2) liver Fgf15/19 signaling. Each of these aims has studies that span from cell culture based approaches to dissect the signaling pathways, mice VSG surgery, and translational human studies to validate our findings.

描述（由申请人提供）：减肥手术仍然是迄今为止最有效、最持久的肥胖治疗选择。更重要的是，除了减肥之外，减肥手术还具有许多有利的代谢作用，包括解决晚期肥胖相关肝病或非酒精性脂肪性肝炎（NASH）。脂肪变性（肝细胞中的脂肪）是 NASH 的定义要素、肝硬化发展的先兆以及肝移植的潜在需求。特别是，我们研究了称为垂直袖状胃切除术 (VSG) 的减肥手术对 NASH 解决的潜在影响。同时，我们观察到接受 VSG 手术的小鼠血清胆汁酸和下游胆汁酸信号传导增加。重要的是，这些影响不仅仅是体重减轻的结果，因为我们的数据表明，在通过食物限制减轻等量体重的啮齿动物中，并没有观察到 NASH 的消退和血清胆汁酸的增加。这些研究建立在我们之前的工作基础上，其中我们研究了其他减肥程序及其对胆汁酸驱动信号的影响。其中包括“回肠转位”或胆汁改道等实验程序，以及 roux-en Y 胃旁路术和可调节胃束带等既定程序。在本提案中，Kohli 博士将重点研究使用肥胖小鼠模型进行 VSG 手术后 NASH 消退的机制。他提案的具体目标是检查特定胆汁酸触发肠道信号、成纤维细胞生长因子 15/19 (Fgf15/1) 的作用。在相互关联的目标中，Kohli 博士建议研究（目标 1）肠道的机制； （目标 2）肝脏 Fgf15/19 信号传导。每个目标都进行了研究，包括基于细胞培养的方法来剖析信号通路、小鼠 VSG 手术以及用于验证我们的发现的转化人体研究。