Todd Porter, Ph.D.
Elevated serum cholesterol is a major factor in the development of cardiovascular diseases such as coronary heart disease and stroke. Although the initial steps in cholesterol synthesis are well described, the downstream pathway for cholesterol synthesis, from squalene to cholesterol, is relatively poorly characterized, despite its importance to physiology and medicine. My laboratory uses recombinant DNA techniques, enzymology, structural biology and proteomics approaches to characterize squalene monooxygenase, the rate-limiting step in this downstream pathway.
Squalene monooxygenase is a 64-kDa flavoprotein bound to the endoplasmic reticulum. Squalene monooxygenase activity is modulated by supernatant protein factor, a 46-kDa cytosolic protein that is thought to serve as a carrier of squalene into and between intracellular membranes. The activity of supernatant protein factor is, in turn, regulated both at the level of expression and, more immediately, through phosphorylation by protein kinases A and C. We are studying the interplay between supernatant protein factor, squalene monooxygenase, protein kinases, and cholesterol levels, in an effort to define the mechanisms that regulate sterol synthesis in the cell.
- Riddick, D.S., Ding, X., Wolf, C.R., Porter, T.D., Pandey, A.V., Zhang, Q.-Y., Gu, J., Finn, R.D., Ronseaux, S., McLaughlin, L.A., Henderson, C.J., Zou, L., and Flück, C.E. (2013) Symposium Report, NADPH-Cytochrome P450 oxidoreductase: Roles in physiology, pharmacology, and toxicology. Drug Metab. Dispos. 41, 12-23.
- Banerjee, S., Ghoshal, S., and Porter, T.D. (2012) Phosphorylation of hepatic AMP-activated protein kinase and LKB1 is increased after a single oral dose of green tea extract to mice. Nutr. Res. 32, 985-990.
- Porter, T.D. (2012) New insights into the role of cytochrome P450 reductase (POR) in microsomal redox biology (Invited review). Acta Pharmaceutica Sinica B 2, 100-104.
- Zou, L., Li, L., and Porter, T.D. (2011) 7-Dehydrocholesterol reductase activity is independent of cytochrome P450 reductase. J. Steroid Biochem. Mol. Biol. 127, 435-438.
- Porter, T.D., Banerjee, S., Stolarczyk, E.I., and Zou, L. (2011) Suppression of cytochrome P450 reductase expression in hepatoma cells replicates the hepatic lipidosis observed in hepatic POR-null mice. Drug Metab. Dispos. 39, 966-973.
- Banerjee, S., Ghoshal, S., and Porter, T.D. (2011) Activation of AMP-kinase by policosanol requires peroxisomal metabolism. Lipids 46, 311-321.
- Li, L., and Porter, T.D. (2009) Chlorzoxazone hydroxylation in microsomes and hepatocytes from cytochrome P450 oxidoreductase-null mice. J. Biochem. Mol. Toxicol. 23, 357-363.
- Singh, D.K., Banerjee, S., and Porter, T.D. (2009) Green and black tea extracts inhibit HMG-CoA reductase and activate AMP-kinase to decrease cholesterol synthesis in hepatoma cells. J. Nutr. Biochem. 20, 816-822.
- Li, L., and Porter, T.D. (2007) Hepatic cytochrome P450 reductase-null mice reveal a second microsomal reductase for squalene monooxygenase. Arch. Biochem. Biophys. 461, 76-84.
- Singh, D.K., Li, L., Porter, T.D. (2006) Policosanol inhibits cholesterol synthesis in hepatoma cells by activation of AMP-kinase. J. Pharmacol. Exp. Ther. 318, 1020-1026.
- Li, L., Pan, R.-M., Porter, T.D., Jensen, N.S., Silber, P., Russo, G., Tine, J.A., Heim, J., Ring, B., and Wedlund, P.J. (2006) New cytochrome P450-2D6*56 allele identified by genotype/phenotype analysis of cryopreserved human hepatocytes. Drug Metab. Dispo. 34, 1411-1416.
- Singh, D.K., and Porter, T.D. (2006) Inhibition of sterol 4a-methyl oxidase is the principal mechanism by which garlic decreases cholesterol synthesis. J. Nutr. 136, 759S-764S.
- Mokashi, V., and Porter, T.D. (2005) Supernatant protein factor requires phosphorylation and interaction with Golgi to stimulate cholesterol synthesis in hepatoma cells. Arch. Biochem. Biophys. 435, 175-181.
- Mokashi, V., Singh, D.K., and Porter, T.D. (2005) Supernatant protein factor stimulates HMG-CoA reductase in cell culture and in vitro. Arch. Biochem. Biophys. 433, 474-480.
- Mokashi, V., Singh, D.K., and Porter, T.D. (2004) Rat supernatant protein factor-like protein stimulates squalene monooxygenase and is activated by protein kinase A. Biochem. Biophys. Res. Commun. 316, 688-692.
- Porter, T.D. (2004) Jud Coon: 35 Years of P450 research, a synopsis of P450 history. Drug Metab. Dispos. 32, 1-6.
- Mokashi, V., Li, L., and Porter, T.D. (2003) Cytochrome b5 reductase and cytochrome b5 support the CYP2E1-mediated activation of nitrosamines in a recombinant Ames test. Arch. Biochem. Biophys. 412, 147-152.
- Singh, D.K., Mokashi, V., Elmore, C.L., and Porter, T.D. (2003) Phosphorylation of supernatant protein factor enhances its ability to stimulate microsomal squalene monooxygenase. J. Biol. Chem. 278, 5646-5651.
- Porter, T.D. (2003) Supernatant protein factor and tocopherol-associated protein: An unexpected link between cholesterol synthesis and vitamin E (Invited review). J. Nutr. Biochem. 14, 3-6.