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

 描述（由申请人提供）：减肥手术仍然是迄今为止最有效和最持久的肥胖治疗选择。更重要的是，除了减肥，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的定义元素和肝硬化发展的前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消退的有效影响。同时，我们在接受VSG手术的小鼠中观察到血清胆汁酸和下游胆汁酸信号的增加。重要的是，这些效应不仅仅是体重减轻的结果，因为我们的数据显示，在通过食物限制减轻等量体重的啮齿动物中未观察到NASH的消退和血清胆汁酸的增加。这些研究建立在我们先前的工作基础上，其中我们研究了其他减肥方法及其对胆汁酸驱动信号的影响。这些方法包括实验性手术，如“回肠转位”或胆汁分流术，以及已建立的手术，如Roux-en Y胃旁路术和可调节胃束带。在本提案中，Kohli博士将使用肥胖小鼠模型重点研究VSG手术后NASH消退的机制。他的建议的具体目标将检查特定胆汁酸触发的肠道信号，成纤维细胞生长因子15/19（Fgf 15/1）的影响。在相互关联的目标中，Kohli博士建议研究（目标1）肠道和（目标2）肝脏Fgf 15/19信号传导的机制。这些目标中的每一个都有研究，涵盖基于细胞培养的方法来剖析信号通路、小鼠VSG手术和转化人类研究，以验证我们的发现。

 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.