TRAIL receptor deletion in mice suppresses the inflammation of nutrient excess

Leila Idrissova, Harmeet M Malhi, Nathan W. Werneburg, Nathan K LeBrasseur, Steven F. Bronk, Christian Fingas, Tamar Tchkonia, Tamar Pirtskhalava, Thomas A. White, Michael B. Stout, Petra Hirsova, Anuradha Krishnan, Christian Liedtke, Christian Trautwein, Niklas Finnberg, Wafik S. El-Deiry, James L Kirkland, Gregory James Gores

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

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<sup>-/-</sup>) mice and their littermate wild-type (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 (BMDMo) was measured. Results Genetic deletion of TR completely repressed weight gain, adiposity and insulin resistance in FFC-fed mice. Moreover, TR<sup>-/-</sup> 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<sup>-/-</sup> BMDMO manifest reduced chemotaxis and diminished activation of nuclear factor-κ 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.

Original languageEnglish (US)
Pages (from-to)1156-1163
Number of pages8
JournalJournal of Hepatology
Volume62
Issue number5
DOIs
StatePublished - May 1 2015

Fingerprint

TNF-Related Apoptosis-Inducing Ligand Receptors
Inflammation
Food
Liver
Adipose Tissue
Macrophages
Chemotaxis
Fructose
Fats
Cholesterol
Macrophage Activation
Palmitates
Adiposity
Fatty Liver
Weight Gain
Lipopolysaccharides
Insulin Resistance
Hepatocytes
Triglycerides
Obesity

ASJC Scopus subject areas

  • Hepatology

Cite this

TRAIL receptor deletion in mice suppresses the inflammation of nutrient excess. / Idrissova, Leila; Malhi, Harmeet M; Werneburg, Nathan W.; LeBrasseur, Nathan K; Bronk, Steven F.; Fingas, Christian; Tchkonia, Tamar; Pirtskhalava, Tamar; White, Thomas A.; Stout, Michael B.; Hirsova, Petra; Krishnan, Anuradha; Liedtke, Christian; Trautwein, Christian; Finnberg, Niklas; El-Deiry, Wafik S.; Kirkland, James L; Gores, Gregory James.

In: Journal of Hepatology, Vol. 62, No. 5, 01.05.2015, p. 1156-1163.

Research output: Contribution to journalArticle

Idrissova, L, Malhi, HM, Werneburg, NW, LeBrasseur, NK, Bronk, SF, Fingas, C, Tchkonia, T, Pirtskhalava, T, White, TA, Stout, MB, Hirsova, P, Krishnan, A, Liedtke, C, Trautwein, C, Finnberg, N, El-Deiry, WS, Kirkland, JL & Gores, GJ 2015, 'TRAIL receptor deletion in mice suppresses the inflammation of nutrient excess', Journal of Hepatology, vol. 62, no. 5, pp. 1156-1163. https://doi.org/10.1016/j.jhep.2014.11.033
Idrissova, Leila ; Malhi, Harmeet M ; Werneburg, Nathan W. ; LeBrasseur, Nathan K ; Bronk, Steven F. ; Fingas, Christian ; Tchkonia, Tamar ; Pirtskhalava, Tamar ; White, Thomas A. ; Stout, Michael B. ; Hirsova, Petra ; Krishnan, Anuradha ; Liedtke, Christian ; Trautwein, Christian ; Finnberg, Niklas ; El-Deiry, Wafik S. ; Kirkland, James L ; Gores, Gregory James. / TRAIL receptor deletion in mice suppresses the inflammation of nutrient excess. In: Journal of Hepatology. 2015 ; Vol. 62, No. 5. pp. 1156-1163.
@article{70790009a17a41ea8b062cd00f3a5286,
title = "TRAIL receptor deletion in mice suppresses the inflammation of nutrient excess",
abstract = "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 wild-type (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 (BMDMo) 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-/- BMDMO manifest reduced chemotaxis and diminished activation of nuclear factor-κ 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.",
author = "Leila Idrissova and Malhi, {Harmeet M} and Werneburg, {Nathan W.} and LeBrasseur, {Nathan K} and Bronk, {Steven F.} and Christian Fingas and Tamar Tchkonia and Tamar Pirtskhalava and White, {Thomas A.} and Stout, {Michael B.} and Petra Hirsova and Anuradha Krishnan and Christian Liedtke and Christian Trautwein and Niklas Finnberg and El-Deiry, {Wafik S.} and Kirkland, {James L} and Gores, {Gregory James}",
year = "2015",
month = "5",
day = "1",
doi = "10.1016/j.jhep.2014.11.033",
language = "English (US)",
volume = "62",
pages = "1156--1163",
journal = "Journal of Hepatology",
issn = "0168-8278",
publisher = "Elsevier",
number = "5",

}

TY - JOUR

T1 - TRAIL receptor deletion in mice suppresses the inflammation of nutrient excess

AU - Idrissova, Leila

AU - Malhi, Harmeet M

AU - Werneburg, Nathan W.

AU - LeBrasseur, Nathan K

AU - Bronk, Steven F.

AU - Fingas, Christian

AU - Tchkonia, Tamar

AU - Pirtskhalava, Tamar

AU - White, Thomas A.

AU - Stout, Michael B.

AU - Hirsova, Petra

AU - Krishnan, Anuradha

AU - Liedtke, Christian

AU - Trautwein, Christian

AU - Finnberg, Niklas

AU - El-Deiry, Wafik S.

AU - Kirkland, James L

AU - Gores, Gregory James

PY - 2015/5/1

Y1 - 2015/5/1

N2 - 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 wild-type (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 (BMDMo) 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-/- BMDMO manifest reduced chemotaxis and diminished activation of nuclear factor-κ 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.

AB - 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 wild-type (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 (BMDMo) 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-/- BMDMO manifest reduced chemotaxis and diminished activation of nuclear factor-κ 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.

UR - http://www.scopus.com/inward/record.url?scp=84927797559&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84927797559&partnerID=8YFLogxK

U2 - 10.1016/j.jhep.2014.11.033

DO - 10.1016/j.jhep.2014.11.033

M3 - Article

C2 - 25445398

AN - SCOPUS:84927797559

VL - 62

SP - 1156

EP - 1163

JO - Journal of Hepatology

JF - Journal of Hepatology

SN - 0168-8278

IS - 5

ER -