Aluminum toxicity triggers the nuclear translocation of HIF-1alpha and promotes anaerobiosis in hepatocytes.
Although aluminum (Al) is known to be toxic, the exact molecular events that enable this trivalent metal to be involved in various diseases have not been fully delineated. In this report, we show that Al promotes the translocation of the HIF-1alpha (hypoxia inducible factor) to the nucleus and activates the anaerobic metabolism of D-glucose. Al-exposed hepatocytes (HepG2 cells) showed a marked increase in HIF-1alpha that was associated with nuclear extracts. D-Glucose consumption in these Al-stressed cells was rapid as more GLUT-1 transporter was expressed. Furthermore, these Al-treated HepG2 cells were characterized with enhanced activities of such metabolic enzymes as hexokinase (HK), pyruvate kinase (PK), lactate dehydrogenase (LDH) and glucose 6-phosphate dehydrogenase (G6PDH). (13)C- NMR studies pointed to a metabolic profile in Al-stressed cells that favored enhanced glycolysis. HPLC analyses confirmed increased glycolytic ATP production in Al-exposed hepatocytes. These findings reveal the ability of Al to create a hypoxic environment that promotes the translocation of HIF-1alpha to the nucleus and stimulates the anaerobic metabolism of D-glucose.
Mailloux
Ryan J
RJ
Department of Chemistry and Biochemistry, Laurentian University, Sudbury, Ont., Canada P3E 2C6.
Appanna
Vasu D
VD
D000255:Adenosine Triphosphate / Q000378:metabolism; D000535:Aluminum / Q000633:toxicity*; D000693:Anaerobiosis / Q000187:drug effects*; D002458:Cell Fractionation; D002460:Cell Line; D004591:Electrophoresis, Polyacrylamide Gel; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D015151:Immunoblotting; D050356:Lipid Metabolism / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy; D010084:Oxidation-Reduction; D010427:Pentose Phosphate Pathway / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects*
D051272:Glucose Transporter Type 1; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000255:Adenosine Triphosphate; D000535:Aluminum; D005947:Glucose