TRAIL receptor deletion in mice suppresses the inflammation of nutrient excess

JOURNAL OF HEPATOLOGY

卷:62

Article

Idrissova, Leila¹  Malhi, Harmeet¹  Werneburg, Nathan W.¹  LeBrasseur, Nathan K.²  Bronk, Steven F.¹  Fingas, Christian¹  Tchkonia, Tamar²  Pirtskhalava, Tamar²  White, Thomas A.²  Stout, Michael B.²  Hirsova, Petra¹  Krishnan, Anuradha¹  Liedtke, Christian³  Trautwein, Christian³  Finnberg, Niklas⁴  El-Deiry, Wafik S.⁴  Kirkland, James L.²  Gores, Gregory J.¹ 

[1] Mayo Clin, Div Gastroenterol & Hepatol, Rochester, MN 55905 USA

[2] Mayo Clin, Robert & Arlene Kogod Ctr Aging, Rochester, MN 55905 USA

[3] Univ Hosp, Dept Med 3, Aachen, Germany

[4] Penn State Hershey Canc Inst, Hershey, PA 17033 USA

关键词: Non-alcoholic fatty liver disease;    Metainflammation;    Lipoapoptosis;    Macrophage activation;   

DOI  :  10.1016/j.jhep.2014.11.033

来源: Elsevier

【 摘 要 】

Background & Aims: Low-grade chronic inflammation is a cardinal feature of the metabolic syndrome, yet its pathogenesis is not well defined. The purpose of this study was to examine the role of TRAIL receptor (TR) signaling in the pathogenesis of obesity-associated inflammation using mice with the genetic deletion of TR. Methods: TR knockout (TR-/-) mice and their littermate wildtype (WT) mice were fed a diet high in saturated fat, cholesterol and fructose (FFC) or chow. Metabolic phenotyping, liver injury, and liver and adipose tissue inflammation were assessed. Chemotaxis and activation of mouse bone marrow-derived macrophages (BMDM phi) was measured. Results: Genetic deletion of TR completely repressed weight gain, adiposity and insulin resistance in FFC-fed mice. Moreover, TR-/- mice suppressed steatohepatitis, with essentially normal serum ALT, hepatocyte apoptosis and liver triglyceride accumulation. Gene array data implicated inhibition of macrophage-associated hepatic inflammation in the absence of the TR. In keeping with this, there was diminished accumulation and activation of inflammatory macrophages in liver and adipose tissue. TR-/- BMDM phi manifest reduced chemotaxis and diminished activation of nuclear factor-kappa B signaling upon activation by palmitate and lipopolysaccharide. Conclusions: These data advance the concept that macrophage-associated hepatic and adipose tissue inflammation of nutrient excess requires TR signaling. (C) 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

【 授权许可】

Free