Dr. Peter Edwards' research focuses on cholesterol and its role in various diseases. A number of new signaling molecules/hormones that include oxysterols and bile acids have recently been identified. These compounds bind to and activate the transcription factors/nuclear receptors, LXR and FXR, respectively. Edwards and his colleagues are interested in the identification of the induced genes, the mechanism of gene activation and the function of the induced proteins. The researchers utilize microarray technology, cells that have been stably or transiently transfected with either wild-type, dominant positive or dominant negative nuclear receptors, and transgenic and null mice to address some of these questions.
Edwards' studies have led to the identification of novel genes whose mRNAs are induced when macrophages are treated with oxycholesterols, low density lipoprotein or ligands for LXR. These treatments convert macrophages to macrophage foam cells, a cell type important in the development of atherosclerosis. Edwards has concluded that, in macrophage foam cells, the nuclear receptor LXR plays a central role in the activation of genes encoding ABCG1, PLTP, apolipoprotein E, C-I, C-II, C-IV. The data suggest that increased expression of these proteins serves both to protect the macrophage from lipid loading and to alter lipoprotein metabolism in the artery wall. He and his associates are particularly interested in the function of one LXR target gene called ABCG1. ABCG1 is a member of the ATP binding cassette family of trans-membrane transporters that we hypothesize controls the efflux of lipids out of the cells.
The researchers are also interested in the effects produced when bile acids activate the farnesoid receptor (FXR). The novel observation that bile acids function as hormones makes this area particularly interesting. Edwards' lab has used a variety of approaches to identify FXR target genes that include PLTP, apoC-II, and MRP2. These genes are all involved in controlling blood lipid levels and/or lipid excretion into the bile. The importance of FXR is being tested further in vivo using both null and transgenic mice. Thus, activation of FXR may prove to be useful in the treatment of hypertriglyceridemia and/or cholestasis.
Both FXR and LXR currently are of great interest to both academics and pharmaceutical companies, since it is hypothesized that regulation of the target genes may result in a reduction in blood lipids and/or a decrease in foam cell formation/atherosclerosis. Ideally, the current collaborations between industry and the Edwards laboratory will provide insights into the importance of FXR and LXR in both normal and diseased states.
Selected Cancer-Related Publications:
Zhang Y, Lee FY, Barrera G, Lee H, Vales C, Gonzalez FJ, Willson TM, Edwards PA. Activation of the nuclear receptor FXR improves hyperglycemia and hyperlipidemia in diabetic mice. Proc Natl Acad Sci U S A. 2006; 103(4): 1006-11.
Bald?n A, Pei L, Lee R, Tarr P, Tangirala RK, Weinstein MM, Frank J, Li AC, Tontonoz P, Edwards PA. Impaired development of atherosclerosis in hyperlipidemic Ldlr-/- and ApoE-/- mice transplanted with Abcg1-/- bone marrow. Arterioscler Thromb Vasc Biol. 2006; 26(10): 2301-7.
Bald?n A, Tarr P, Vales CS, Frank J, Shimotake TK, Hawgood S, Edwards PA. Deletion of the transmembrane transporter ABCG1 results in progressive pulmonary lipidosis. J Biol Chem. 2006; 281(39): 29401-10.
Kennedy MA, Barrera GC, Nakamura K, Bald?n A, Tarr P, Fishbein MC, Frank J, Francone OL, Edwards PA. ABCG1 has a critical role in mediating cholesterol efflux to HDL and preventing cellular lipid accumulation. Cell Metab. 2005; 1(2): 121-31.
Zhang Y, Castellani LW, Sinal CJ, Gonzalez FJ, Edwards PA. Peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC-1alpha) regulates triglyceride metabolism by activation of the nuclear receptor FXR. Genes Dev. 2004; 18(2): 157-69.