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- W2113485484 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. We found deficient GH-dependent signal transducer and activator of transcription (STAT)-5 signaling correlates with steatosis, and through microarray analysis, quantitative PCR, and chromatin immunoprecipitation, identifies 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, we have used the hepatoma line DN-STAT5a/b, DN-STAT1, CA-STAT3, or addition of oleate/palmitate to assign which of these apply to individual targets in active STAT5 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 expression may also contribute. In conclusion, despite normal plasma free fatty acids and minimal obesity, absent GH activation leads to steatosis because phosphorylated STAT5 prevents hepatic steatosis. These results raise the possibility of low-dose GH treatment for nonalcoholic fatty liver disease." @default.
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- W2113485484 date "2010-12-01" @default.
- W2113485484 modified "2023-09-26" @default.
- W2113485484 title "GH (Growth Hormone)-Dependent STAT5 Signaling Plays an Important Role in Hepatic Lipid Metabolism" @default.
- W2113485484 doi "https://doi.org/10.1210/edrv.31.6.9977" @default.
- W2113485484 hasPublicationYear "2010" @default.
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