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

基本信息

批准号：
9244018
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
项目类别：
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/9244018
关键词：
Abdomen Acids Adolescent Adolescent obesity Adult Adverse effects Affect Agonist Alpha Cell 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 nonalcoholic steatohepatitis novel public health relevance receptor relating to nervous system success

项目摘要

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（适用提供）：减肥手术仍然是迄今为止肥胖症最有效，最耐用的治疗选择。更重要的是，除了减肥外，减肥手术还具有许多有利的代谢作用，包括分辨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）是定义纳什的元素和肝硬化发展的先驱和肝移植的潜在需求。特别是，我们研究了称为垂直袖胃切除术（VSG）对NASH分辨率的减肥手术的潜在影响。同时，我们观察到接受VSG手术的小鼠中血清胆汁酸和下游胆汁酸信号传导增加。重要的是，这些影响不仅是体重减轻的结果，因为我们的数据表明，在通过食物限制的啮齿动物中，nash的分辨率和血清胆汁酸的增加没有看到。这些研究以我们先前的工作为基础，我们研究了其他减肥手术及其对胆汁酸驱动信号的影响。其中包括实验程序，例如“回肠换位”或胆汁转移，以及诸如roux-en y胃旁路和可调节胃体的既定程序。在这项建议中，Kohli博士将使用肥胖的鼠模型在VSG手术后重点介绍NASH分辨率的机制。他的建议的具体目的将检查特定的胆汁酸触发肠道信号的作用，成纤维细胞生长因子15/19（FGF15/1）。在相互关联的目标中，科利博士提出了研究（AIM 1）肠的机制；（AIM 2）肝FGF15/19信号传导。这些目标中的每一个都有从基于细胞培养的方法进行研究的研究，以剖析信号通路，小鼠VSG手术，并翻译人类研究以验证我们的发现。