Differential proteomic analysis of STAT6 knockout mice reveals new regulatory function in liver lipid homeostasis.
Increased inflammatory signaling is a key feature of metabolic disorders. In this context, the role of increased pro-inflammatory signals has been extensively studied. By contrast, no efforts have been dedicated to study the contrasting scenario: the attenuation of anti-inflammatory signals and their role in metabolic homeostasis. IL-4 and IL-13 are anti-inflammatory cytokines signaling through the Signal Transducer and Activator of Transcription 6 (STAT6). Our study was aimed at evaluating the lack of STAT6 signaling on liver homeostasis. To this end we analyzed the liver proteome of wild type and STAT6 knock-out mice using 2D nanoscale LC-MS/MS with iTRAQ labeling technique. The coordinated changes in proteins identified by this quantitative proteome analysis indicated disturbed lipid homeostasis and a state of hepatocellular stress. Most significantly, the expression of the liver fatty acid binding protein (FABP1) was increased in the knock-out mice. In line with the elevated FABP1 expression we found latent liver lipid accumulation in the STAT6-deficient mice which was further aggravated when mice were challenged by a high fat diet. In conclusion, our study revealed a so far uncharacterized role for STAT6 in regulating liver lipid homeostasis and demonstrates the importance of anti-inflammatory signaling in the defense against the development of liver steatosis.
Iff
Joël
J
Department of Cellular Physiology and Metabolism, University of Geneva, Switzerland.
Wang
Wei
W
Sajic
Tatjana
T
Oudry
Nathalie
N
Gueneau
Estelle
E
Hopfgartner
Gérard
G
Varesio
Emmanuel
E
Szanto
Ildiko
I
D000818:Animals; D003198:Computer Simulation; D050556:Fatty Acid-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D006360:Heat-Shock Proteins; D007150:Immunohistochemistry; D007553:Isotope Labeling; D050356:Lipid Metabolism / Q000502:physiology*; D008099:Liver / Q000378:metabolism*; D008297:Male; D013058:Mass Spectrometry / Q000379:methods; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic; D020543:Proteome / Q000378:metabolism; D040901:Proteomics / Q000379:methods*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D050800:STAT6 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism
C493320:Fabp1 protein, mouse; D050556:Fatty Acid-Binding Proteins; D006360:Heat-Shock Proteins; D020543:Proteome; D050796:STAT3 Transcription Factor; D050800:STAT6 Transcription Factor; C491411:Socs3 protein, mouse; C494087:Stat3 protein, mouse; C494100:Stat6 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins