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.

PUBLIC HEALTH RELEVANCE: Bariatric surgeries such as the sleeve gastrectomy surgery are now an accepted treatment of morbid obesity and its associated liver co-morbidity - fatty liver disease. The severe form of fatty liver disease is predicted to become the number one cause for liver transplantation in adults in the United States over the next couple of decades. This proposal seeks to identify the key mechanisms involved behind the success of sleeve gastrectomy to provide potential targets for "bariatric mimetic technologies" that would produce less risk but similar benefits to a much larger percentage of the at-risk population.