Cazanave, Xuan Wang, Huiping Zhou, Curtis D. Klaassen Obesity is a primary risk factor for the development of non-alcoholic fatty liver disease (NAFLD), a spectrum of disorders ranging from steatosis to steatohepatitis to cirrhosis. NAFLD has become the most common

chronic liver disease in the developed world. The twinned observations that obesity is associated with increased activation of the IL-17 axis and that this axis can regulate liver damage in diverse contexts prompted us to address the role of IL-17RA signaling in the progression of NAFLD. IL-17RA-deficient mice were subjected to obesogenic diet stress (a standard model of diet-induced obesity and NAFLD) or a regular diet as a control. Development of obesity, pro-inflammatory cytokine production, glucose dysmetabolism, buy Kinase Inhibitor Library hepatic triglyceride accumulation and inflammation

and hepatocellular damage were analyzed. Additionally, by colonizing or depleting an intestinal commensal, known to drive IL-17 production, we examined the role of intestinal microbe-driven IL-17 induction in progression of NAFLD in WT and Leptin receptor mutant mice (Leprdb/db). Notably, our data indicate that IL-17RA-/- mice respond to obesogenic diet stress with significantly greater weight gain, visceral adiposity, and hepatic steatosis selleckchem than wild type controls. However, obesity-driven lipid accumulation was uncoupled from its end organ consequences in IL-17RA-/- mice, which exhibited decreased steatohepatitis, NADPH-oxidase enzyme expression and hepatocellular damage and were protected from glucose dysmetabolism. Further, antibody-mediated neutralization of IL-17A significantly reduced obesity associated hepatocellular damage in wild type mice. Lastly, colonization of mice with segmented filamentous bacteria (SFB), a commensal that induces Th17 differentiation, elevated systemic IL-17A production and exacerbated obesityinduced hepatocellular damage. Similarly, selective (though not specific) SFB depletion suppressed

IL-17A production check and protected from obesity-induced hepatocellular damage. These data indicate that obesity-driven activation of the IL-17 axis is central to the development and progression of NAFLD and identify the IL-17 pathway as a novel therapeutic target in NAFLD. Ongoing studies aim at defining the biologically-relevant IL-17RA expressing cell types, IL-17RA ligands and molecular pathways central to the IL-17 axis mediated progression of NASH. Disclosures: Rohit Kohli – Grant/Research Support: Johnson and Johnson, Johnson and Johnson The following people have nothing to disclose: Daniel Giles, Traci Stankiewicz, Isaac T. Harley, Monica Cappelletti, Samir Softic, Stavra A. Xanthakos, Christopher L. Karp, Senad Divanovic Elevated serum bile acids suppress bile acid synthesis and lipogenesis after vertical sleeve gastrectomy (VSG) is performed in obese mice.