ISR target genes in the liver of either LFD and HFD-treated Alb::GC mice and AP20187-treated TTR::Fv2E-PERK mice

The molecular mechanisms linking the stress of unfolded proteins in the endoplasmic reticulum (ER stress) to glucose intolerance in obese animals are poorly understood. In this study enforced expression of a translation initiation 2alpha (eIF2a)-specific phosphatase, GADD34, was used to selectively compromise signaling in the eIF2(P)-dependent arm of the ER unfolded protein response in liver of transgenic mice. The transgene resulted in lower liver glycogen levels and susceptibility to fasting hypoglycemia in lean mice and glucose tolerance and diminished hepato-steatosis in animals fed a high fat diet. Attenuated eIF2(aP) correlated with lower expression of the adipogenic nuclear receptor PPARgamma and its upstream regulators, the transcription factors C/EBPalpha and C/EBPbeta, in transgenic mouse liver, whereas eIF2alpha phosphorylation promoted C/EBP translation in cultured cells and primary hepatocytes. These observations suggest that eIF2(aP)-mediated translation

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Oyadomari S, Harding HP, Zhang Y, Oyadomari M, Ron D