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IL‐17 signaling accelerates the progression of nonalcoholic fatty liver disease in mice
Author(s) -
Harley Isaac T.W.,
Stankiewicz Traci E.,
Giles Daniel A.,
Softic Samir,
Flick Leah M.,
Cappelletti Monica,
Sheridan Rachel,
Xanthakos Stavra A.,
Steinbrecher Kris A.,
Sartor R. Balfour,
Kohli Rohit,
Karp Christopher L.,
Divanovic Senad
Publication year - 2014
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.26746
Subject(s) - nonalcoholic fatty liver disease , steatosis , fatty liver , endocrinology , inflammation , medicine , nadph oxidase , nicotinamide adenine dinucleotide phosphate , biology , oxidative stress , oxidase test , disease , enzyme , biochemistry
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. Conclusion : 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. (H epatology 2014;59:1830–1839)