Selective Up-regulation of LXR-regulated Genes ABCA1, ABCG1, and APOE in Macrophages through Increased Endogenous Synthesis of 24(S),25-Epoxycholesterol

Liver X receptor (LXR) activation represents a mechanism to prevent macrophage foam cell formation. Previously, we demonstrated that partial inhibition of oxidosqualene:lanosterol cyclase (OSC) stimulated synthesis of the LXR agonist 24(S),25-epoxycholesterol (24(S),25-epoxy) and enhanced ABCA1-mediated cholesterol efflux. In contrast to a synthetic, nonsteroidal LXR activator, TO-901317, triglyceride accumulation was not observed. In the present study, we determined whether endogenous 24(S),25-epoxy synthesis selectively enhanced expression of macrophage LXR-regulated cholesterol efflux genes but not genes that regulate fatty acid metabolism. THP-1 human macrophages incubated with the OSC inhibitor (OSCi) RO0714565 (15 nm) significantly reduced cholesterol synthesis and maximized synthesis of 24(S),25-epoxy. Endogenous 24(S),25-epoxy increased ABCA1, ABCG1, and APOE mRNA abundance and consequently increased cholesterol efflux to apoAI. In contrast, OSCi had no effect on LXR-regulated genes LPL (lipoprotein lipase) and FAS (fatty acid synthase). TO-901317 (≥10 nm) significantly enhanced expression of all genes examined. OSCi and TO-901317 increased the mRNA and precursor form of SREBP-1c, a major regulator of fatty acid and triglyceride synthesis. However, conversion of the precursor to the active form (nSREBP-1c) was blocked by OSCi-induced 24(S),25-epoxy but not by TO-901317 (≥10 nm), which instead markedly increased nSREBP-1c. Disruption of nSREBP-1c formation by 24(S),25-epoxy accounted for diminished FAS and LPL expression. In summary, endogenous synthesis of 24(S),25-epoxy selectively up-regulates expression of macrophage LXR-regulated cholesterol efflux genes without stimulating genes linked to fatty acid and triglyceride synthesis. Liver X receptor (LXR) activation represents a mechanism to prevent macrophage foam cell formation. Previously, we demonstrated that partial inhibition of oxidosqualene:lanosterol cyclase (OSC) stimulated synthesis of the LXR agonist 24(S),25-epoxycholesterol (24(S),25-epoxy) and enhanced ABCA1-mediated cholesterol efflux. In contrast to a synthetic, nonsteroidal LXR activator, TO-901317, triglyceride accumulation was not observed. In the present study, we determined whether endogenous 24(S),25-epoxy synthesis selectively enhanced expression of macrophage LXR-regulated cholesterol efflux genes but not genes that regulate fatty acid metabolism. THP-1 human macrophages incubated with the OSC inhibitor (OSCi) RO0714565 (15 nm) significantly reduced cholesterol synthesis and maximized synthesis of 24(S),25-epoxy. Endogenous 24(S),25-epoxy increased ABCA1, ABCG1, and APOE mRNA abundance and consequently increased cholesterol efflux to apoAI. In contrast, OSCi had no effect on LXR-regulated genes LPL (lipoprotein lipase) and FAS (fatty acid synthase). TO-901317 (≥10 nm) significantly enhanced expression of all genes examined. OSCi and TO-901317 increased the mRNA and precursor form of SREBP-1c, a major regulator of fatty acid and triglyceride synthesis. However, conversion of the precursor to the active form (nSREBP-1c) was blocked by OSCi-induced 24(S),25-epoxy but not by TO-901317 (≥10 nm), which instead markedly increased nSREBP-1c. Disruption of nSREBP-1c formation by 24(S),25-epoxy accounted for diminished FAS and LPL expression. In summary, endogenous synthesis of 24(S),25-epoxy selectively up-regulates expression of macrophage LXR-regulated cholesterol efflux genes without stimulating genes linked to fatty acid and triglyceride synthesis. Macrophage-derived cholesteryl ester-rich foam cells develop within the arterial wall as a result of excessive internalization of lipoproteins, which subsequently promote early atherosclerotic plaque formation. In addition, foam cells enhance susceptibility to plaque rupture within advanced stage lesions, leading to further atherosclerosis complications (1Linton M.F. Fazio S. Int. J. Obes. Relat. Metab. Disord. 2003; 27 (Suppl. 3): 35-40Crossref PubMed Scopus (225) Google Scholar, 2Takahashi K. Takeya M. Sakashita N. Med. Electron Microsc. 2002; 35: 179-203Crossref PubMed Scopus (143) Google Scholar). The ligand-activated nuclear receptors known as liver X receptors (LXRs), 5The abbreviations used are: LXR, liver X receptor; LXRE, LXR response element; SRE, sterol response element; 24(S),25-epoxy, 24(S),25-epoxycholesterol; OSC, 2,3-oxidosqualene:lanosterol cyclase; OSCi, OSC inhibitor; PDB, phorbol 12,13-dibutyrate; 25-OH, 25-hydroxycholesterol; 22(R)-OH, 22(R)-hydroxycholesterol; LDL, low density lipoprotein; acLDL, acetylated LDL; LPDS, lipoprotein-deficient serum; qRT, quantitative real time reverse transcription; pSREBP-1, precursor SREBP-1; nSREBP-1, nuclear SREBP-1; SCAP, sterol cleavage-activating protein; INSIG, insulin-signaling protein; DMHCA, N,N-dimethyl-3β-hydroxycholenamide. 5The abbreviations used are: LXR, liver X receptor; LXRE, LXR response element; SRE, sterol response element; 24(S),25-epoxy, 24(S),25-epoxycholesterol; OSC, 2,3-oxidosqualene:lanosterol cyclase; OSCi, OSC inhibitor; PDB, phorbol 12,13-dibutyrate; 25-OH, 25-hydroxycholesterol; 22(R)-OH, 22(R)-hydroxycholesterol; LDL, low density lipoprotein; acLDL, acetylated LDL; LPDS, lipoprotein-deficient serum; qRT, quantitative real time reverse transcription; pSREBP-1, precursor SREBP-1; nSREBP-1, nuclear SREBP-1; SCAP, sterol cleavage-activating protein; INSIG, insulin-signaling protein; DMHCA, N,N-dimethyl-3β-hydroxycholenamide. whose natural ligands are oxysterols, regulate the expression of genes involved in lipid homeostasis through binding to LXR response elements (LXREs) within the promoter of several responsive genes. These include ABCA1 (ATP-binding cassette A1), ABCG1, and APOE (apolipoprotein E), which mediate cellular cholesterol efflux from human and mouse macrophages to extracellular acceptors (3Tontonoz P. Mangelsdorf D.J. Mol. Endocrinol. 2003; 17: 985-993Crossref PubMed Scopus (519) Google Scholar). Additionally, activated LXR increases expression of SREBP-1c (sterol regulatory element-binding protein 1c), FAS (fatty acid synthase), and LPL (lipoprotein lipase), which together act to stimulate cellular free fatty acid synthesis and free fatty acid uptake, respectively, leading to enhanced triglyceride synthesis (4Yoshikawa T. Shimano H. Amemiya-Kudo M. Yahagi N. Hasty A.H. Matsuzaka T. Okazaki H. Tamura Y. Iizuka Y. Ohashi K. Osuga J. Harada K. Gotoda T. Kimura S. Ishibashi S. Yamada N. Mol. Cell Biol. 2001; 21: 2991-3000Crossref PubMed Scopus (430) Google Scholar, 5Joseph S.B. Laffitte B.A. Patel P.H. Watson M.A. Matsukuma K.E. Walczak R. Collins J.L. Osborne T.F. Tontonoz P. J. Biol. 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In vivo experiments using a synthetic, nonsteroidal LXR agonist, TO-901317, established that LXR activation is integral in attenuating atherosclerosis (10Joseph S.B. McKilligin E. Pei L. Watson M.A. Collins A.R. Laffitte B.A. Chen M. Noh G. Goodman J. Hagger G.N. Tran J. Tippin T.K. Wang X. Lusis A.J. Hsueh W.A. Law R.E. Collins J.L. Willson T.M. Tontonoz P. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 7604-7609Crossref PubMed Scopus (768) Google Scholar, 11Terasaka N. Hiroshima A. Koieyama T. Ubukata N. Morikawa Y. Nakai D. Inaba T. FEBS Lett. 2003; 536: 6-11Crossref PubMed Scopus (289) Google Scholar). Although the precise underlying mechanisms are not fully understood, reduction in macrophage foam cell formation by enhancing cholesterol efflux probably plays a significant role. LXR activation in mice directly stimulates reverse cholesterol transport as determined by tracing radiolabeled sterols from macrophages to plasma high density lipoprotein and subsequently into the liver and bile (12Naik S.U. Wang X. Da Silva J.S. Jaye M. Macphee C.H. Reilly M.P. Billheimer D.J. PubMed Scopus Google Scholar). of in mice in enhanced S.B. Walczak R. Laffitte B.A. D. Mangelsdorf D.J. Wang X. Lusis A.J. Tontonoz P. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: PubMed Scopus Google Scholar), atherosclerosis M. C. J. D.J. M.A. Cell Metab. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar), further the of LXR activation in The major effect of of mice with LXR is a in plasma and liver triglyceride (10Joseph S.B. McKilligin E. Pei L. Watson M.A. Collins A.R. Laffitte B.A. Chen M. Noh G. Goodman J. Hagger G.N. Tran J. Tippin T.K. Wang X. Lusis A.J. Hsueh W.A. Law R.E. Collins J.L. Willson T.M. Tontonoz P. Proc. Natl. Acad. Sci. U. S. 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Previously, we demonstrated that inhibition of OSC by RO0714565 a that 24(S),25-epoxy synthesis enhanced cholesterol efflux from mouse effect with in the expression of ABCA1 and In contrast to the synthetic, nonsteroidal LXR agonist TO-901317, OSC inhibition not to accumulation of cellular to the of in nuclear A.H. 2003; PubMed Scopus Google Scholar). However, the underlying mechanism for effect was not In the present study, we that enhanced synthesis of 24(S),25-epoxy within a to significant increases in the expression of LXR-regulated genes ABCA1, ABCG1, and APOE and cholesterol and SREBP-1c THP-1 macrophages to OSC inhibitor (OSCi) a that endogenous 24(S),25-epoxy synthesis. ABCA1, ABCG1, and APOE expression as was cholesterol efflux. However, expression of genes involved in fatty acid FAS and was not was in fatty acid triglyceride LPL OSCi-induced 24(S),25-epoxy 24(S),25-epoxy increased SREBP-1c mRNA and precursor However, of TO-901317, the OSCi-induced 24(S),25-epoxy 24(S),25-epoxy blocked conversion of the to active nuclear which probably for the of enhanced FAS and LPL expression. Cell and human THP-1 cell was from cells in with and and with phorbol for to in experiments as C.H. J. Biol. Chem. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). The OSCi as RO0714565 with of for human liver OSC was by J. and in In cells incubated with 24(S),25-epoxy, in the synthetic, nonsteroidal LXR TO-901317 in was from human by and acetylated using as J.L. Proc. Natl. Acad. Sci. U. S. A. 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The OSCi in a in ABCA1 protein to to 24(S),25-epoxy and increased ABCA1 protein abundance and respectively, and increased ABCA1 protein TO-901317 of and increased ABCA1 protein and significant in cell protein the protein of the not that the used not cell THP-1 cells incubated with of to the of ABCA1 protein in with cells and of increased ABCA1 protein in the and OSC inhibition increased mRNA abundance of and APOE and 24(S),25-epoxy, 22(R)-OH, and TO-901317 nm) increased and APOE to a with However, the in APOE in the of and TO-901317 nm) was not significant APOE mRNA abundance was significantly increased in the of The expression of ABCA1, ABCG1, and APOE was with a in efflux of cholesterol to no effect was in the of 24(S),25-epoxy, 22(R)-OH, and TO-901317 increased cholesterol efflux to with and TO-901317 nm) increased cholesterol efflux to OSCi FAS mRNA 24(S),25-epoxy the LXR agonist TO-901317, not stimulate triglyceride accumulation activation of LXR-regulated genes within mouse macrophages A.H. 2003; PubMed Scopus Google Scholar). FAS expression and fatty acid and triglyceride synthesis in human THP-1 macrophages incubated with the OSCi the LXR The OSCi had no significant on FAS mRNA 24(S),25-epoxy 22(R)-OH, low TO-901317 The and of TO-901317 increased expression of FAS and with OSCi, 24(S),25-epoxy, 22(R)-OH, TO-901317 not fatty acid synthesis triglyceride synthesis which with the of in FAS mRNA abundance for In contrast, and of TO-901317 significantly increased fatty acid synthesis and to and triglyceride synthesis and to OSC on LPL LPL expression in macrophages accumulation of fatty of and increases the of cholesteryl ester-rich foam cell formation J. Full Text Full Text PDF PubMed Google Scholar). we LPL mRNA abundance in the of OSCi, we no significant in mRNA with was no in LPL with the OSCi 24(S),25-epoxy, 22(R)-OH, TO-901317 had no effect on LPL mRNA abundance on LPL TO-901317 and increased LPL mRNA and LPL was significantly increased with TO-901317 and with TO-901317, LPL increased and with and TO-901317 LPL was by all SREBP-1c mRNA and by OSC of into of genes through binding to through expression of SREBP-1c and binding of nSREBP-1c to within the promoter H. Yahagi N. Amemiya-Kudo M. Hasty A.H. Osuga J. Tamura Y. Iizuka Y. Ohashi K. Harada K. Gotoda T. Ishibashi S. Yamada N. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). However, of expression binding of LXR and nSREBP-1c to and SRE, S.B. Laffitte B.A. Patel P.H. Watson M.A. Matsukuma K.E. Walczak R. Collins J.L. Osborne T.F. Tontonoz P. J. Biol. Chem. 2002; 277: 11019-11025Abstract Full Text Full Text PDF PubMed Scopus (611) Google Scholar). OSCi not the mRNA abundance of LPL SREBP-1c mRNA and protein abundance within macrophages in to the mechanism expression of genes in triglyceride SREBP-1c mRNA was increased significantly in the of OSCi with 24(S),25-epoxy of and increased SREBP-1c mRNA and respectively, and TO-901317 enhanced SREBP-1c abundance and with TO-901317 SREBP-1c expression in a and of and mRNA abundance was by the OSCi 24(S),25-epoxy not of the of cell a to and a protein in the nuclear to active was by the OSCi, and of 24(S),25-epoxy increased and The increases in with and TO-901317 not TO-901317 and in a and In contrast, the OSCi, 24(S),25-epoxy TO-901317 nm) not with significantly abundance The of 24(S),25-epoxy also had no effect on and with the of TO-901317 and which and Previously, to protein in cells J. L. J.L. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar) and cells E. S. 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The activation of LXR-regulated genes we in human THP-1 cells and experiments in mouse macrophages A.H. 2003; PubMed Scopus Google Scholar). In ABCA1 and transcription leading to increased cholesterol cellular triglyceride synthesis and abundance and LPL The mechanism for activation of LXR-regulated genes was not fully In the study, the significant OSCi-induced in SREBP-1c mRNA and pSREBP-1, cellular of the active nuclear form not that conversion was are with a mechanism the in LXR-regulated expression was to the OSCi-induced synthesis of 24(S),25-epoxy. in cells incubated with 24(S),25-epoxy, a that increased ABCA1 expression to the as cells incubated with the of 24(S),25-epoxy, ABCA1 expression increased protein and FAS expression the that 24(S),25-epoxy the formation of In contrast, the nonsteroidal LXR activator, TO-901317, of no and increased the expression of all LXR-regulated genes examined. the increased SREBP-1c mRNA and protein to a significant in and consequently FAS and LPL mRNA low of TO-901317 nm), the expression of ABCA1, ABCG1, and SREBP-1c increased in THP-1 cells to the as with the LPL and FAS fatty and triglyceride synthesis and not significantly that was the for activation of genes involved in fatty acid metabolism. of and of by LXR and on the of agonist Mangelsdorf D.J. 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Gelman L. Haby C. Briggs M. Auwerx J. J. Mol. Biol. 2000; 304: 323-334Crossref PubMed Scopus (65) Google Scholar, M.J. Moon Y.S. Kim K.H. Sul H.S. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 10619-10624Crossref PubMed Scopus (140) Google Scholar, L.M. Deng X. Wilcox H.G. Park E.A. Raghow R. Elam M.B. Biochem. J. 2005; 385: 207-216Crossref PubMed Scopus (125) Google Scholar), such as SREBP-1c, and FAS to LXR and SREBP-1c in a to transcription S.B. Laffitte B.A. Patel P.H. Watson M.A. Matsukuma K.E. Walczak R. Collins J.L. Osborne T.F. Tontonoz P. J. Biol. Chem. 2002; 277: 11019-11025Abstract Full Text Full Text PDF PubMed Scopus (611) Google Scholar) and consequently to and lipid In contrast to oxysterols, the of TO-901317 to prevent as demonstrated in the present study, in enhanced formation of nSREBP-1c from abundance of leading to increased expression of genes and cellular triglyceride Endogenous of 24(S),25-epoxy LXR but of FAS LPL expression. the mechanism of activation of LXR-regulated genes by 24(S),25-epoxy the LXR agonist a LXR agonist was to selectively LXR-regulated genes in THP-1 macrophages A.R. Chen L. P. J. Full Text Full Text PDF PubMed Scopus Google Scholar). with TO-901317 increased ABCA1 and expression to a the increases in SREBP-1c and FAS of that for Although increased cholesterol efflux in THP-1 the of on of fatty acid and triglyceride accumulation not A.R. Chen L. P. J. 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Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). on in the inhibition of OSC in vivo of cholesterol and the enhanced synthesis of 24(S),25-epoxy for the reduction of lipid in liver and we that of OSCi to and plasma cholesterol without in to activation of LXR-regulated and in liver and P.H. H. Biol. 2005; PubMed Scopus Google Scholar). to to In summary, that partial inhibition of OSC a mechanism of of cholesterol homeostasis cholesterol for the synthesis OSC inhibition 24(S),25-epoxy which selectively LXR-regulated genes involved in cholesterol efflux without a in fatty acid triglyceride synthesis. The OSCi, was to the on the that the human (OSC) was in The of human OSC, which that are R. T. J. J. H. M. M. A. PubMed Scopus Google Scholar), the and synthesis of to the synthesis of 24(S),25-epoxy. OSC inhibition a mechanism to foam cell formation through activation of genes that promote cholesterol efflux as a result of enhanced endogenous synthesis of the LXR agonist 24(S),25-epoxy.

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