The role of HNF-1alpha in controlling hepatic catalase activity.
Mice deficient in hepatocyte nuclear factor 1alpha (HNF-1alpha) develop Laron dwarfism and non-insulin-dependent diabetes mellitus (Lee et al., 1998). Oxidative stress was present in the diabetic HNF-1alpha-null mice. To understand the mechanism underlying the oxidative stress in HNF-1alpha-null mice, we examined whether HNF-1alpha deficiency affects the integrity of the cellular defense system against oxidative stress. The glutathione level and activities of superoxide dismutase and glutathione reductase in liver and other tissues examined were not affected by HNF-1alpha deficiency. However, activities of cytosolic glutathione peroxidase and catalase, two enzymes responsible for detoxification of hydrogen peroxide within cells, were reduced specifically in liver of HNF-1alpha-null mice. The mRNA and protein levels of hepatic catalase in HNF-1alpha-null mice did not differ from those in normal mice. The loss of hepatic catalase activity in HNF-1alpha-null mice is probably caused by an insufficient heme pool in liver cells, because the mRNA level of ferrochelatase, the enzyme that catalyzes the last step of heme biosynthesis, was significantly reduced in liver, and the daily hemin treatment restored partial catalase activity in liver of HNF-1alpha-null mice. Furthermore, our results of cell transfection and luciferase reporter assay indicated that the mouse ferrochelatase promoter could be trans-activated directly by HNF-1alpha.
Muppala
V
V
Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan.
Lin
C S
CS
Lee
Y H
YH
D000375:Aging / Q000378:metabolism; D000818:Animals; D002374:Catalase / Q000378:metabolism*; D002522:Chlorocebus aethiops; D004268:DNA-Binding Proteins; D005294:Ferrochelatase / Q000096:biosynthesis / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic; D005979:Glutathione Peroxidase / Q000378:metabolism; D006418:Heme / Q000378:metabolism; D006427:Hemin / Q000494:pharmacology; D051537:Hepatocyte Nuclear Factor 1; D051538:Hepatocyte Nuclear Factor 1-alpha; D051539:Hepatocyte Nuclear Factor 1-beta; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D066298:In Vitro Techniques; D008099:Liver / Q000201:enzymology*; D051379:Mice; D009687:Nuclear Proteins; D018384:Oxidative Stress; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis / Q000378:metabolism; D014157:Transcription Factors / Q000172:deficiency / Q000502:physiology*; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; C496487:HNF1A protein, human; C496495:HNF1B protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; C496488:Hnf1a protein, mouse; C496496:Hnf1b protein, mouse; D009687:Nuclear Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D051537:Hepatocyte Nuclear Factor 1; D051539:Hepatocyte Nuclear Factor 1-beta; D006418:Heme; D006427:Hemin; D006861:Hydrogen Peroxide; D002374:Catalase; D005979:Glutathione Peroxidase; D005294:Ferrochelatase