GH-dependent STAT5 signaling plays an important role in hepatic lipid metabolism

Barclay, JL, Nelson, CN, Ishikawa, M, Murray, LA, Kerr, LM, McPhee, TR, Powell, EE and Waters, MJ (2011) GH-dependent STAT5 signaling plays an important role in hepatic lipid metabolism. Endocrinology, 152 1: 181-192. doi:10.1210/en.2010-0537


Author Barclay, JL
Nelson, CN
Ishikawa, M
Murray, LA
Kerr, LM
McPhee, TR
Powell, EE
Waters, MJ
Title GH-dependent STAT5 signaling plays an important role in hepatic lipid metabolism
Journal name Endocrinology   Check publisher's open access policy
ISSN 0013-7227
1945-7170
Publication date 2011-01-01
Year available 2010
Sub-type Article (original research)
DOI 10.1210/en.2010-0537
Volume 152
Issue 1
Start page 181
End page 192
Total pages 12
Place of publication Chevy Chase, MD, United States
Publisher The Endocrine Society
Collection year 2011
Language eng
Formatted abstract
GH deficiency is known to be clinically associated with a high incidence of nonalcoholic fatty liver disease, and this can be reversed by GH administration. Here we investigated the mechanistic basis for this phenomenon using engineered male mice lacking different signaling elements of the GH receptor, hepatic stat5a/b-/-mice and a mouse hepatoma line.Wefound deficient GH-dependent signal transducer and activator of transcription (STAT)-5 signaling correlates with steatosis, and through microarray analysis, quantitative PCR, and chromatin immunoprecipitation, identified putative targets of STAT5 signaling responsible for the steatosis seen on a normal diet. These targets were verified with liver-specific stat5a/b deletion in vivo, and in vitro we show that dominant-negative (DN) STAT5 increases lipid uptake in a mouse hepatoma line. Because loss of STAT5 signaling results in elevated STAT1 and STAT3 activity and intracellular lipid accumulation,wehave used DN-STAT5a/b, DN-STAT1, constitutively active (CA)-STAT3, or addition of oleate/palmitate in thehepatomaline to assign which of these apply to individual targets inSTAT5signaling deficiency. These findings and published mouse models of steatosis enable us to propose elevated cd36, pparγ, and pgc1α/β expression as primary instigators of the steatosis along with elevated fatty acid synthase, lipoprotein lipase, and very low-density lipoprotein receptor expression. Decreased fgf21 and insig2 expressionmayalso contribute. In conclusion, despite normal plasma free fatty acids and minimal obesity, absent GH activation leads to steatosis because activated STAT5 prevents hepatic steatosis. These results raise the possibility of low-dose GH treatment for nonalcoholic fatty liver disease.
Copyright © 2010 The Endocrine Society. All rights reserved.
Keyword Growth-hormone receptor
Proliferator-activated receptors
Nonalcoholic fatty liver
Gene-expression
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Published online before print November 17, 2010.

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2011 Collection
Institute for Molecular Bioscience - Publications
 
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Created: Sun, 30 Jan 2011, 10:05:59 EST