The main objective of this proposal is to study the first specific enzyme in the cholesterol biosynthetic pathway in the liver, squalene synthetase, in order to understand the mechanisms of its regulation. This objective is now attainable since we recently isolated, purified and obtained partial protein sequences of the rat liver squalene synthetase protein as well as cDNA clones for both the rat and the human enzymes. This, in turn, will enable us to clone and study the regulation of the enzyme. The mechanisms of regulation of rat hepatic squalene synthetase at the transcription, translation and protein level will be examined under wide variations of cholesterogenesis. The contribution of the variations of the activity of this enzyme to the diversion of common intermediates, specifically trans-farnesyl pyrophosphate, to sterol and nonsterol products (the flux diversion hypothesis) will be examined. Examination and comparison of 5'flanking regions of the squalene synthetase gene to other known regulatory enzymes in this pathway may explain the complex regulation of the mevalonate branched pathway. Cloning and the understanding of the regulation of squalene synthetase, the most specific enzyme in the cholesterol biosynthetic pathway, may allow the development of compounds that will interact with, and change the activity of this enzyme and therefore, may serve as cholesterol lowering drugs.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Metabolism Study Section (MET)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Eleanor Roosevelt Institute for Cancer Research
United States
Zip Code
Shechter, Ishaiahu; Dai, Peihua; Roseman, Mark A et al. (2003) Low-temperature effect on the sterol-dependent processing of SREBPs and transcription of related genes in HepG2 cells. J Lipid Res 44:1581-90
Shechter, Ishaiahu; Dai, Peihua; Huo, Liang et al. (2003) IDH1 gene transcription is sterol regulated and activated by SREBP-1a and SREBP-2 in human hepatoma HepG2 cells: evidence that IDH1 may regulate lipogenesis in hepatic cells. J Lipid Res 44:2169-80
Guan, Guimin; Dai, Peihua; Shechter, Ishaiahu (2003) cDNA cloning and gene expression analysis of human myo-inositol 1-phosphate synthase. Arch Biochem Biophys 417:251-9
Tansey, T R; Shechter, I (2001) Squalene synthase: structure and regulation. Prog Nucleic Acid Res Mol Biol 65:157-95
Tansey, T R; Shechter, I (2000) Structure and regulation of mammalian squalene synthase. Biochim Biophys Acta 1529:49-62
Chen, H T; Mehan, R S; Gupta, S D et al. (1999) Involvement of farnesyl protein transferase (FPTase) in FcarepsilonRI-induced activation of RBL-2H3 mast cells. Arch Biochem Biophys 364:203-8
Gupta, S D; Mehan, R S; Tansey, T R et al. (1999) Differential binding of proteins to peroxisomes in rat hepatoma cells: unique association of enzymes involved in isoprenoid metabolism. J Lipid Res 40:1572-84
Guan, G; Dai, P; Shechter, I (1998) Differential transcriptional regulation of the human squalene synthase gene by sterol regulatory element-binding proteins (SREBP) 1a and 2 and involvement of 5' DNA sequence elements in the regulation. J Biol Chem 273:12526-35
Guan, G; Dai, P H; Osborne, T F et al. (1997) Multiple sequence elements are involved in the transcriptional regulation of the human squalene synthase gene. J Biol Chem 272:10295-302
Memon, R A; Shechter, I; Moser, A H et al. (1997) Endotoxin, tumor necrosis factor, and interleukin-1 decrease hepatic squalene synthase activity, protein, and mRNA levels in Syrian hamsters. J Lipid Res 38:1620-9

Showing the most recent 10 out of 12 publications