The Role of Small Heterodimer Partner (SHP) in NAFLD Improvement after Vertical Sleeve Gastrectomy in Mice

Objective—Bile acids (BA) are elevated after vertical sleeve gastrectomy (VSG) and farnesoidX-receptor (FXR) is critical to the success of murine VSG. BA down-regulate hepatic lipogenesis by activating the FXR-small heterodimer partner (SHP) pathway. We tested the role of SHP in fatty liver disease (NAFLD) improvement after VSG. Design and Methods—Wild type (WT), SHP liver-transgenic (SHP-Tg) and SHP knockout (SHP-KO) high-fat diet (HFD) fed mice underwent either VSG or Sham surgery. Body weight, BA level & composition, steatosis and BA metabolism gene expression were evaluated. Results—Obese WT mice post-VSG lost weight, reduced steatosis, decreased plasma alanine aminotransferase (ALT), had more BA absorptive ileal area, and elevated serum BA. Obese SHPTg mice post-VSG also lost weight and had decreased steatosis. SHP-KO mice were however resistant to steatosis despite weight gain on a HFD. Further SHP-KO mice that underwent VSG lost weight but developed hepatic inflammation and had increased ALT. Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms Corresponding author contact information: Rohit Kohli, MBBS, MS, Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, MLC 2010, 3333 Burnet Avenue, Cincinnati, Ohio, USA, 45229. Tel.: 1-513-803-0908, Fax: 1-513-803-2785, [email protected]. Conflicts of Interest Statement: The other coauthors have no disclosures. Author Contributions: AM, RMSG, and RK conceived and carried out experiments, LM, KKR, KDRS, LW, and RJS conceived experiments and analyzed data. WZ, PJ carried out experiments. All authors were involved in writing the manuscript and had final approval of the submitted and published versions. HHS Public Access Author manuscript Obesity (Silver Spring). Author manuscript; available in PMC 2015 November 01. Published in final edited form as: Obesity (Silver Spring). 2014 November ; 22(11): 2301–2311. doi:10.1002/oby.20890. A uhor M anscript