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Department of Surgery, F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814-4799
1 To whom correspondence should be addressed. e-mail: ishechter{at}usuhs.mil
The mRNA level for cytosolic NADP-dependent isocitrate dehydrogenase (IDH1) increases 2.3-fold, and enzyme activity of NADP-isocitrate dehydrogenase (IDH) 63%, in sterol-deprived HepG2 cells. The mRNA levels of the NADP- and NAD-dependent mitochondrial enzymes show limited or lack of regulation under the same conditions. Nucleotide sequences that are required, and sufficient, for the sterol regulation of transcription are located within a 67 bp region of an IDH1-secreted alkaline phosphatase promoter-reporter gene. The IDH1 promoter is fully activated by the expression of SREBP-1a in the cells and, to a lesser degree, by that of SREBP-2. A 5'-end truncation of 23 bp containing a CAAT and a GC-Box results in 6.5% residual activity. The promoter region involved in the activation by the sterol regulatory element binding proteins (SREBPs) is located at nucleotides -44 to -25. Mutagenesis analysis identified within this region the IDH1-SRE sequence element GTGGGCTGAG, which binds the SREBPs. Similar to the promoter activation, electrophoretic mobility shifts of probes containing the IDH1-SRE element exhibit preferential binding to SREBP-1a, as compared with SREBP-2.
These results indicate that IDH1 activity is coordinately regulated with the cholesterol and fatty acid biosynthetic pathways and suggest that it is the source for the cytosolic NADPH required by these pathways.
Abbreviations: HSS, human squalene synthase; IDH, isocitrate dehydrogenase; IDH1, cytosolic NADP-dependent IDH; IDH2, mitochondrial NADP-dependent IDH; IDH3, mitochondrial NAD-dependent IDH; PPAR, peroxisome proliferator-activated receptor; RXR, retinoid X receptor; SCAP, SREBP cleavage-activating protein; SEAP, secreted alkaline phosphatase; SQS, squalene synthase; SRE, sterol regulatory element; SREBP, sterol regulatory element binding protein
Supplementary key words cytosolic NADP-dependent IDH • sterol regulatory element binding protein • fatty acid synthesis • transcriptional regulation • cholesterogenesis
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