Endoplasmic reticulum stress increases glucose-6-phosphatase and glucose cycling in liver cells.
Impaired regulation of hepatic glucose production is a characteristic feature of the metabolic syndrome, a cluster of diseases that includes obesity, insulin resistance, type 2 diabetes, and cardiovascular disease. It has been proposed that sustained endoplasmic reticulum stress, which appears to occur in obesity and diabetes, modulates insulin action in the liver. In this study, we show that experimental induction of endoplasmic reticulum stress increases expression and activity of glucose-6-phosphatase and the capacity for glucose release and glucose cycling in primary rat hepatocytes and H4IIE liver cells. Increased expression of the catalytic subunit of glucose-6-phosphatase was largely a result of increased transcription. Deletion analysis of the glucose-6-phosphatase promoter identified an endoplasmic reticulum stress-responsive region located between -233 and -187 with respect to the transcriptional start site. Experimental induction of endoplasmic reticulum stress increased the activity of c-jun N-terminal kinase. Prevention of endoplasmic reticulum stress-mediated activation of c-jun N-terminal kinase reduced the expression of the catalytic subunit of glucose-6-phosphatase, glucose-6-phosphatase activity, glucose release, and glucose cycling. These data demonstrate that sustained endoplasmic reticulum stress in the hepatocyte provokes adaptations, mediated in part via activation of c-jun N-terminal kinase, that act to increase hepatocellular capacity for glucose release and glucose cycling.
Wang
Dong
D
Departments of Food Science and Human Nutrition, Colorado State University, Fort Collins, Colorado 80523-1571, USA.
Wei
Yuren
Y
Schmoll
Dieter
D
Maclean
Kenneth N
KN
Pagliassotti
Michael J
MJ
D000818:Animals; D017931:DNA Primers; D004721:Endoplasmic Reticulum / Q000502:physiology*; D005947:Glucose / Q000378:metabolism*; D005952:Glucose-6-Phosphatase / Q000235:genetics* / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism*; D007700:Kinetics; D008099:Liver / Q000502:physiology; D008297:Male; D010766:Phosphorylation; D016133:Polymerase Chain Reaction / Q000379:methods; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar
D017931:DNA Primers; D012333:RNA, Messenger; D005952:Glucose-6-Phosphatase; D005947:Glucose