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:
Hong C, Kidani Y, A-Gonzalez N, Phung T, Ito A, Rong X, Ericson K, Mikkola H, Beaven SW, Miller LS, Shao WH, Cohen PL, Castrillo A, Tontonoz P, Bensinger SJ. Coordinate regulation of neutrophil homeostasis by liver X receptors in mice. J Clin Invest. 2012 Jan 3;122(1):337-47. Epub 2011 Dec 12
Scotti E, Hong C, Yoshinaga Y, Tu Y, Hu Y, Zelcer N, Boyadjian R, de Jong PJ, Young SG, Fong LG, Tontonoz P. Targeted disruption of the idol gene alters cellular regulation of the low-density lipoprotein receptor by sterols and liver x receptor agonists. Mol Cell Biol. 2011 May;31(9):1885-93. Epub 2011 Feb 22
Guo D, Reinitz F, Youssef M, Hong C, Nathanson D, Akhavan D, Kuga D, Amzajerdi AN, Soto H, Zhu S, Babic I, Tanaka K, Dang J, Iwanami A, Gini B, Dejesus J, Lisiero DD, Huang TT, Prins RM, Wen PY, Robins HI, Prados MD, Deangelis LM, Mellinghoff IK, Mehta MP, James CD, Chakravarti A, Cloughesy TF, Tontonoz P, Mischel PS. An LXR agonist promotes glioblastoma cell death through inhibition of an EGFR/AKT/SREBP-1/LDLR-dependent pathway. Cancer Discov. 2011 Oct;1(5):442-56. Epub 2011 Sep 15
A-Gonzalez N, Bensinger SJ, Hong C, Beceiro S, Bradley MN, Zelcer N, Deniz J, Ramirez C, Díaz M, Gallardo G, de Galarreta CR, Salazar J, Lopez F, Edwards P, Parks J, Andujar M, Tontonoz P, Castrillo A. Apoptotic cells promote their own clearance and immune tolerance through activation of the nuclear receptor LXR. Immunity. 2009 Aug 21;31(2):245-58. Epub 2009 Jul 30
Bensinger SJ, Bradley MN, Joseph SB, Zelcer N, Janssen EM, Hausner MA, Shih R, Parks JS, Edwards PA, Jamieson BD, Tontonoz P. LXR signaling couples sterol metabolism to proliferation in the acquired immune response. Cell. 2008 Jul 11;134(1):97-111.