Abstract
Mice deficient in hepatocyte nuclear factor 1α (HNF-1α) develop Laron dwarfism and non-insulin-dependent diabetes mellitus (Lee et al., 1998). Oxidative stress was present in the diabetic HNF-1α-null mice. To understand the mechanism underlying the oxidative stress in HNF-1α-null mice, we examined whether HNF-1α 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-1α 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-1α-null mice. The mRNA and protein levels of hepatic catalase in HNF-1α-null mice did not differ from those in normal mice. The loss of hepatic catalase activity in HNF-1α-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-1α-null mice. Furthermore, our results of cell transfection and luciferase reporter assay indicated that the mouse ferrochelatase promoter could betrans-activated directly by HNF-1α.
Footnotes
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Send reprint requests to: Dr. Ying-Hue Lee, Institute of Molecular Biology, Academia Sinica, Taipei 115, Taiwan. E-mail:mbying{at}ccvax.sinica.edu.tw
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This work was supported in part by Research Grant NSC-88–2311-B-001–106 and NSC-89–2311-001–078 from the National Science Council of Taiwan.
- Abbreviations:
- HNF-1α
- hepatocyte nuclear factor 1α
- IGF-I
- insulin-like growth factor I
- GPx
- glutathione peroxidase
- FC
- ferrochelatase
- MDA
- malonaldehyde
- SOD
- superoxide dismutase
- C/EBPα
- CCAAT enhancer binding protein
- HNF4
- hepatocyte nuclear factor 4
- GR
- glutathione reductase
- Received June 17, 1999.
- Accepted September 30, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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