title: IL-17 signaling accelerates the progression of nonalcoholic fatty liver disease in mice.
abstract: Inflammation plays a central pathogenic role in the pernicious metabolic and end-organ sequelae of obesity. Among these sequelae, nonalcoholic fatty liver disease (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 interleukin (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. We further examined whether microbe-driven IL-17A regulated NAFLD development and progression. We show here that IL-17RA(-/-) mice respond to high-fat diet stress with significantly greater weight gain, visceral adiposity, and hepatic steatosis than wild-type controls. However, obesity-driven lipid accumulation was uncoupled from its end-organ consequences in IL-17RA(-/-) mice, which exhibited decreased steatohepatitis, nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase enzyme expression, and hepatocellular damage. Neutralization of IL-17A significantly reduced obesity-driven hepatocellular damage in wild-type mice. Further, colonization of mice with segmented filamentous bacteria (SFB), a commensal that induces IL-17A production, exacerbated obesity-induced hepatocellular damage. In contrast, SFB depletion protected from obesity-induced hepatocellular damage.
  
  
  CONCLUSIONS
  These data indicate that obesity-driven activation of the IL-17 axis is central to the development and progression of NAFLD to steatohepatitis and identify the IL-17 pathway as a novel therapeutic target in this condition.
authors.affiliation: Division of Cellular and Molecular Immunology, Cincinnati Children's Hospital Research Foundation, and the University of Cincinnati College of Medicine, Cincinnati, OH.
authors.forename: Isaac T W
authors.initials: IT
authors.lastname: Harley
authors.forename: Traci E
authors.initials: TE
authors.lastname: Stankiewicz
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Giles
authors.forename: Samir
authors.initials: S
authors.lastname: Softic
authors.forename: Leah M
authors.initials: LM
authors.lastname: Flick
authors.forename: Monica
authors.initials: M
authors.lastname: Cappelletti
authors.forename: Rachel
authors.initials: R
authors.lastname: Sheridan
authors.forename: Stavra A
authors.initials: SA
authors.lastname: Xanthakos
authors.forename: Kris A
authors.initials: KA
authors.lastname: Steinbrecher
authors.forename: R Balfour
authors.initials: RB
authors.lastname: Sartor
authors.forename: Rohit
authors.initials: R
authors.lastname: Kohli
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Karp
authors.forename: Senad
authors.initials: S
authors.lastname: Divanovic
mesh_terms: D000818:Animals; D001424:Bacterial Infections / Q000150:complications; D059305:Diet, High-Fat; D018450:Disease Progression; D005234:Fatty Liver / Q000209:etiology* / Q000382:microbiology; D007249:Inflammation / Q000209:etiology; D020381:Interleukin-17 / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease; D009765:Obesity / Q000150:complications; D017382:Reactive Oxygen Species / Q000378:metabolism; D053722:Receptors, Interleukin-17 / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*
chemical_list: C491673:Il17ra protein, mouse; D020381:Interleukin-17; D017382:Reactive Oxygen Species; D053722:Receptors, Interleukin-17