scholarly journals FoxO1 Links Hepatic Insulin Action to Endoplasmic Reticulum Stress

Endocrinology ◽  
2010 ◽  
Vol 151 (8) ◽  
pp. 3521-3535 ◽  
Author(s):  
Adama Kamagate ◽  
Dae Hyun Kim ◽  
Ting Zhang ◽  
Sandra Slusher ◽  
Roberto Gramignoli ◽  
...  

Forkhead box O1 (FoxO1) is a transcription factor that mediates the inhibitory effect of insulin on target genes in hepatic metabolism. Hepatic FoxO1 activity is up-regulated to promote glucose production during fasting and is suppressed to limit postprandial glucose excursion after meals. Increased FoxO1 activity augments the expression of insulin receptor (IR) and IR substrate (IRS)2, which in turn inhibits FoxO1 activity in response to reduced insulin action. To address the underlying physiology of such a feedback loop for regulating FoxO1 activity, we delivered FoxO1-ADA by adenovirus-mediated gene transfer into livers of adult mice. FoxO1-ADA is a constitutively active allele that is refractory to insulin inhibition, allowing us to determine the metabolic effect of a dislodged FoxO1 feedback loop in mice. We show that hepatic FoxO1-ADA production resulted in significant induction of IR and IRS2 expression. Mice with increased FoxO1-ADA production exhibited near glycogen depletion. Unexpectedly, hepatic FoxO1-ADA production elicited a profound unfolded protein response, culminating in the induction of hepatic glucose-regulated protein 78 (GRP78) expression. These findings were recapitulated in primary human and mouse hepatocytes. FoxO1 targeted GRP78 gene for trans-activation via selective binding to an insulin responsive element in the GRP78 promoter. This effect was counteracted by insulin. Our studies underscore the importance of an IR and IRS2-dependent feedback loop to keep FoxO1 activity in check for maintaining hepatic glycogen homeostasis and promoting adaptive unfolded protein response in response to altered metabolism and insulin action. Excessive FoxO1 activity, resulting from a dislodged FoxO1 feedback loop in insulin resistant liver, is attributable to hepatic endoplasmic reticulum stress and metabolic abnormalities in diabetes.

2003 ◽  
Vol 23 (21) ◽  
pp. 7448-7459 ◽  
Author(s):  
Ann-Hwee Lee ◽  
Neal N. Iwakoshi ◽  
Laurie H. Glimcher

ABSTRACT The mammalian unfolded protein response (UPR) protects the cell against the stress of misfolded proteins in the endoplasmic reticulum (ER). We have investigated here the contribution of the UPR transcription factors XBP-1, ATF6α, and ATF6β to UPR target gene expression. Gene profiling of cell lines lacking these factors yielded several XBP-1-dependent UPR target genes, all of which appear to act in the ER. These included the DnaJ/Hsp40-like genes, p58IPK, ERdj4, and HEDJ, as well as EDEM, protein disulfide isomerase-P5, and ribosome-associated membrane protein 4 (RAMP4), whereas expression of BiP was only modestly dependent on XBP-1. Surprisingly, given previous reports that enforced expression of ATF6α induced a subset of UPR target genes, cells deficient in ATF6α, ATF6β, or both had minimal defects in upregulating UPR target genes by gene profiling analysis, suggesting the presence of compensatory mechanism(s) for ATF6 in the UPR. Since cells lacking both XBP-1 and ATF6α had significantly impaired induction of select UPR target genes and ERSE reporter activation, XBP-1 and ATF6α may serve partially redundant functions. No UPR target genes that required ATF6β were identified, nor, in contrast to XBP-1 and ATF6α, did the activity of the UPRE or ERSE promoters require ATF6β, suggesting a minor role for it during the UPR. Collectively, these results suggest that the IRE1/XBP-1 pathway is required for efficient protein folding, maturation, and degradation in the ER and imply the existence of subsets of UPR target genes as defined by their dependence on XBP-1. Further, our observations suggest the existence of additional, as-yet-unknown, key regulators of the UPR.


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