Glucose deprivation induces heme oxygenase-1 gene expression by a pathway independent of the unfolded protein response.
Nutrients such as glucose regulate the expression of genes that are involved in plasma membrane transport, metabolic functions, and protein trafficking in the endoplasmic reticulum. Depletion of nutrients results in cellular stress, which evokes adaptive and protective responses, one of which is the induction of heme oxygenase-1 (HO-1), a 32-kDa endoplasmic reticulum enzyme that catalyzes the rate-limiting step in heme degradation. Incubation of HepG2 human hepatoma cells in glucose-free medium resulted in an increased HO-1 mRNA content, reaching a maximum of approximately 25-fold over control cells after 12 h. The glucose-dependent induction of HO-1 mRNA was concentration-dependent (k(12) approximately 0.5 mm) and was attenuated by fructose, galactose, mannose, and 2-deoxyglucose, but not by the non-metabolizable glucose analog, 3-O-methylglucose. Tunicamycin, thapsigargin, or azetidine 2-carboxylate, each of which activates the unfolded protein response pathway, did not induce HO-1 mRNA expression, whereas glucose-regulated protein 78 mRNA was increased. These results demonstrate that glucose availability regulates transcription of the HO-1 gene via a pathway that is different from the unfolded protein response. The induction of HO-1 may serve as a protective response in hypoglycemic circumstances and underscores the importance of understanding nutrient control of the HO-1 gene.
Chang
Se-Ho
SH
Department of Medicine, Division of Nephrology, Hypertension & Transplantation and Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, Florida 32610, USA.
Barbosa-Tessmann
Ione
I
Chen
Chin
C
Kilberg
Michael S
MS
Agarwal
Anupam
A
D002384:Catalysis; D002952:Citric Acid Cycle; D015971:Gene Expression Regulation, Enzymologic; D005947:Glucose / Q000378:metabolism*; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics*; D006801:Humans; D007700:Kinetics; D010084:Oxidation-Reduction; D011489:Protein Denaturation; D012333:RNA, Messenger / Q000235:genetics; D014407:Tumor Cells, Cultured
D012333:RNA, Messenger; D006419:Heme Oxygenase (Decyclizing); D005947:Glucose