We hypothesized that SHP activation is necessary for the bile acid induced improvement of hepatic steatosis after VSG. Methods: To induce obesity adult male SHP knockout (SHP KO)mice and their wild type littermates were fed a high saturated fat diet (HFD, 60kcal%) for 8 weeks. Mice were randomized into four groups (n=4-8) viz.; VSG surgery I-BET-762 SHP KO (SHP KO VSG), VSG wild type (WT VSG), Sham surgery SHP KO (SHP KO Sham), Sham wild type (WT Sham). Mice were on liquid diet for three days post-surgery and then back on the HFD. Animals were sacrificed 8 weeks post-surgery. Results: SHP

KO mice were obese (>30g) but had lower body weight compared to their wild type littermates before surgery (p<0.001). Both KO and WT VSG mice lost click here more body weight and had lower body

weight compared to their respective Sham groups at 8 weeks post-surgery (p<0.001). Serum bile acid levels were not different between groups pre-surgery but were higher in both WT and SHP KO VSG groups compared to the Sham operated mice at 2, 4, 6 and 8 weeks postsurgery (fasting) and 8 weeks (post-prandial; p<0.05). As seen before in WT mice, Cyp7a1 (bile acid synthesis) gene expression in SHP KO VSG mice was suppressed compared to SHP KO Sham mice (p<0.001). Liver triglyceride levels were lower in WT VSG group compared to WT Sham (p<0.001) but no difference was observed between SHP KO VSG and SHP KO Sham groups. Further histological steatosis scores

were also not different between SHP KO VSG and SHP KO Sham mice. Plasma ALT levels were lower in WT VSG mice compared to WT Sham (54.86±4.9 U/L vs. 113.7±17.5 上海皓元医药股份有限公司 WT Sham; p<0.05) while no difference was observed between SHP KO VSG and SHP KO Sham mice (102.6±2.0 and 99.60±10.2). Further the NAFLD Activity Score was higher in SHP KO mice that underwent VSG compared to Sham operated SHP KO mice (p<0.05). Conclusions: SHP KO and WT mice both lost more body weight and had increased serum total bile acid levels after VSG surgery. Despite weight loss and bile acid synthesis gene suppression, SHP KO VSG mice had no reduction in hepatic steatosis, triglyceride accumulation or plasma ALT levels. We conclude that having an intact SHP transcription factor is necessary for the improvement in NASH seen after VSG surgery in obese mice though the suppression of bile acid synthesis seen in SHP KO VSG mice maybe SHP independent. Disclosures: Randy J.