Obesity, diabetes, and cardiovascular disease are the leading causes of morbidity and mortality in industrialized societies. The common thread that links these disorders is dysregulation of lipid metabolism. The past few years have seen a new paradigm emerge for the regulation of metabolic pathways with the discovery of specific receptors that are activated by lipids. Included in this group are the peroxisome proliferator-activated receptors PPARgamma and the liver X receptors LXRalpha and beta. Dr. Peter Tontonoz's laboratory is interested in deciphering how regulation of gene expression by these proteins affects physiology and disease.
Tontonoz and his colleagues have shown that a major mechanism whereby lipids regulate gene expression is through direct activation of members of nuclear receptor superfamily. The nuclear receptors LXRa and LXRb are transcriptional regulators of cholesterol absorption, transport, and elimination. In macrophages, LXR signaling is critical for initiating the homeostatic response to cellular lipid loading. Uptake of oxidized LDL leads to increased cellular concentration of oxysterols, the physiologic ligands for LXRs. Activation of LXR induces expression of genes involved in cholesterol efflux including ABCA1, ABCG1, apoE, and PLTP. The end result of this transcriptional cascade is the transfer of excess cholesterol to extracellular acceptors such as apoAI and apoE.
The pathophysiologic significance of the LXR-dependent cholesterol efflux pathway is illustrated by the observations that synthetic LXR ligands reduce atherosclerosis in animal models, whereas loss of macrophage LXR expression dramatically accelerates the disease. Recent studies indicate that in addition to their role in lipid metabolism, LXRs also regulate inflammatory and immune functions. Ligand activation of LXR in macrophages inhibits the expression of NF-kB-dependent inflammatory gene expression induced by LPS, IL-1b, and TNFa. Tontonoz and his colleagues have also shown that bacterial and viral pathogens interfere with macrophage cholesterol metabolism through inhibition of the LXR signaling pathway.
Selected Cancer-Related Publications:
Waki H, Park KW, Mitro N, Pei L, Damoiseaux R, Wilpitz DC, Reue K, Saez E, Tontonoz P. The small molecule harmine is an antidiabetic cell-type-specific regulator of PPARgamma expression. Cell Metab. 2007; 5(5): 357-70.
Pei L, Waki H, Vaitheesvaran B, Wilpitz DC, Kurland IJ, Tontonoz P. NR4A orphan nuclear receptors are transcriptional regulators of hepatic glucose metabolism. Nat Med. 2006; 12(9): 1048-55.
Joseph SB, Bradley MN, Castrillo A, Bruhn KW, Mak PA, Pei L, Hogenesch J, O'connell RM, Cheng G, Saez E, Miller JF, Tontonoz P. LXR-dependent gene expression is important for macrophage survival and the innate immune response. Cell. 2004; 119(2): 299-309.
Joseph SB, Castrillo A, Laffitte BA, Mangelsdorf DJ, Tontonoz P. Reciprocal regulation of inflammation and lipid metabolism by liver X receptors. Nat Med. 2003; 9(2): 213-9.
Castrillo A, Joseph SB, Vaidya SA, Haberland M, Fogelman AM, Cheng G, Tontonoz P. Crosstalk between LXR and toll-like receptor signaling mediates bacterial and viral antagonism of cholesterol metabolism. Mol Cell. 2003; 12(4): 805-16.