2018/01/03 by Ying Liu, Wei Zhuo, Zhuo Wei +10 · 25 citations
Medicine · Biochemistry, Genetics and Molecular Biology · #Cholesterol and Lipid Metabolism #Steroid Chemistry and Biochemistry #Cancer, Lipids, and Metabolism
paper · pdf · doi:10.1194/jlr.m080440
Cholesterol 25-hydroxylase (CH25H) catalyzes the production of 25-hydroxycholesterol (25-HC), an oxysterol that can play an important role in different biological processes. However, the mechanisms regulating CH25H expression have not been fully elucidated. In this study, we determined that CH25H is highly expressed in mouse liver and peritoneal macrophages. We identified several liver X receptor (LXR) response elements (LXREs) in the human CH25H promoter. In HepG2 cells, activation of LXR by 25-HC or other oxysterols and synthetic ligands [T0901317 (T317) and GW3965] induced CH25H protein expression, which was associated with increased CH25H mRNA expression. 25-HC or T317 activated CH25H transcription in an LXRE-dependent manner. Thus, high-expressing LXRα or LXRβ activated CH25H expression, and the activation was further enhanced by LXR ligands. In contrast, inhibition of LXRα/β expression attenuated 25-HC or T317-induced CH25H expression. Deficiency of interferon γ expression reduced, but did not block, LXR ligand-induced hepatic CH25H expression. Activation of LXR also substantially induced macrophage CH25H expression. In vivo, administration of GW3965 to mice increased CH25H expression in both liver and peritoneal macrophages. Taken together, our study demonstrates that 25-HC can activate CH25H expression in an LXR-dependent manner, which may be an important mechanism to exert the biological actions of 25-HC. Cholesterol 25-hydroxylase (CH25H) catalyzes the production of 25-hydroxycholesterol (25-HC), an oxysterol that can play an important role in different biological processes. However, the mechanisms regulating CH25H expression have not been fully elucidated. In this study, we determined that CH25H is highly expressed in mouse liver and peritoneal macrophages. We identified several liver X receptor (LXR) response elements (LXREs) in the human CH25H promoter. In HepG2 cells, activation of LXR by 25-HC or other oxysterols and synthetic ligands [T0901317 (T317) and GW3965] induced CH25H protein expression, which was associated with increased CH25H mRNA expression. 25-HC or T317 activated CH25H transcription in an LXRE-dependent manner. Thus, high-expressing LXRα or LXRβ activated CH25H expression, and the activation was further enhanced by LXR ligands. In contrast, inhibition of LXRα/β expression attenuated 25-HC or T317-induced CH25H expression. Deficiency of interferon γ expression reduced, but did not block, LXR ligand-induced hepatic CH25H expression. Activation of LXR also substantially induced macrophage CH25H expression. In vivo, administration of GW3965 to mice increased CH25H expression in both liver and peritoneal macrophages. Taken together, our study demonstrates that 25-HC can activate CH25H expression in an LXR-dependent manner, which may be an important mechanism to exert the biological actions of 25-HC. 25-Hydroxycholesterol (25-HC) is produced from cholesterol. Although several cytochrome P450 enzymes may complete the conversion of cholesterol into 25-HC in vitro, cholesterol 25-hydroxylase (CH25H) has been demonstrated to play a critical role in the production of 25-HC, both in vitro and in vivo (1.Diczfalusy U. On the formation and possible biological role of 25-hydroxycholesterol.Biochimie. 2013; 95: 455-460Crossref PubMed Scopus (61) Google Scholar). 25-HC can play an important role in different biological processes, particularly in cholesterol metabolism. For instance, at the cellular level, 25-HC inhibits the activity of HMG-CoA reductase (HMGCR) to reduce cholesterol biosynthesis through inactivation of SREBP2 (2.Adams C.M. Reitz J. De Brabander J.K. Feramisco J.D. Li L. Brown M.S. Goldstein J.L. Cholesterol and 25-hydroxycholesterol inhibit activation of SREBPs by different mechanisms, both involving SCAP and Insigs.J. Biol. Chem. 2004; 279: 52772-52780Abstract Full Text Full Text PDF PubMed Scopus (340) Google Scholar). However, mice with deficiency of CH25H expression have intact cholesterol metabolism (3.Reboldi A. Dang E.V. McDonald J.G. Liang G. Russell D.W. Cyster J.G. Inflammation. 25-Hydroxycholesterol suppresses interleukin-1-driven inflammation downstream of type I interferon.Science. 2014; 345: 679-684Crossref PubMed Scopus (297) Google Scholar), which challenges whether 25-HC physiologically functions as a negative regulator of SREBP2 activity and cholesterol biosynthesis. 25-HC also substantially enhances cholesterol esterification by activating ACAT (4.Cheng D. Chang C.C. Qu X. Chang T.Y. Activation of acyl-coenzyme A:cholesterol acyltransferase by cholesterol or by oxysterol in a cell-free system.J. Biol. Chem. 1995; 270: 685-695Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar). Liver X receptor (LXR) α and β are ligand-activated transcription factors. LXR can play several important roles in the regulation of macrophage cholesterol metabolism and hepatic lipogenesis (5.Calkin A.C. Tontonoz P. Transcriptional integration of metabolism by the nuclear sterol-activated receptors LXR and FXR.Nat. Rev. Mol. Cell Biol. 2012; 13: 213-224Crossref PubMed Scopus (534) Google Scholar). For instance, LXR activation by synthetic ligands increases ABCA1 or ABCG1 to enhance excess cellular free cholesterol efflux to the extracellular cholesterol acceptor, apoA-I, or HDL, thereby inhibiting formation of lipid-laden macrophage/foam cells and the development of atherosclerosis (6.Joseph S.B. McKilligin E. Pei L. Watson M.A. Collins A.R. Laffitte B.A. Chen M. Noh G. Goodman J. Hagger G.N. Synthetic LXR ligand inhibits the development of atherosclerosis in mice.Proc. Natl. Acad. Sci. USA. 2002; 99: 7604-7609Crossref PubMed Scopus (775) Google Scholar). In addition to synthetic ligands such as T0901317 (T317) and GW3965, several oxysterols, including 25-HC, can function as endogenous LXR ligands. Thus, 25-HC can also induce macrophage ABCA1/ABCG1 expression in an LXR-dependent manner (7.Zhou X. He W. Huang Z. Gotto Jr., A.M. Hajjar D.P. Han J. Genetic deletion of low density lipoprotein receptor impairs sterol-induced mouse macrophage ABCA1 expression. A new SREBP1-dependent mechanism.J. Biol. Chem. 2008; 283: 2129-2138Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar). However, the effect of 25-HC on foam-cell formation appears controversial. In vitro, treatment of macrophages with 25-HC increases cellular cholesterol accumulation and foam-cell formation. In vivo, a high 25-HC level is found in the atherosclerotic lesion areas of ApoE deficient (ApoE−/−) mice (8.Gold E.S. Ramsey S.A. Sartain M.J. Selinummi J. Podolsky I. Rodriguez D.J. Moritz R.L. Aderem A. ATF3 protects against atherosclerosis by suppressing 25-hydroxycholesterol-induced lipid body formation.J. Exp. Med. 2012; 209: 807-817Crossref PubMed Scopus (107) Google Scholar). Meanwhile, activation of LXR induces expression of SREBP-1 and its target genes in hepatocytes, such as FASN and acetyl-CoA carboxylase 1 (ACC1), which can result in severe lipid accumulation in the liver (9.Grefhorst A. Elzinga of lipogenesis by activation of the liver X receptor to production of low density lipoprotein Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). of 25-HC on inflammation may the have also been Activation of macrophages CH25H expression to of (3.Reboldi A. Dang E.V. McDonald J.G. Liang G. Russell D.W. Cyster J.G. Inflammation. 25-Hydroxycholesterol suppresses interleukin-1-driven inflammation downstream of type I interferon.Science. 2014; 345: 679-684Crossref PubMed Scopus (297) Google Scholar), which the of 25-HC. 25-HC also macrophage expression and G. 25-hydroxycholesterol induces and a in Full Text Full Text PDF PubMed Scopus Google Scholar). In contrast, 25-HC enhances macrophage production E.S. Podolsky I. R.L. Aderem A. 25-Hydroxycholesterol as an of Natl. Acad. Sci. USA. 2014; PubMed Scopus Google Scholar). In cells, 25-HC induces expression of including and in an manner E. A. D. A. P. oxysterols induce the expression of in cells through Full Text Full Text PDF PubMed Scopus Google Scholar). 25-HC is also in other processes. For instance, 25-HC from activated macrophages can receptor A production McDonald J.G. Liang G. Russell D.W. 25-Hydroxycholesterol by macrophages in response to receptor activation suppresses A Natl. Acad. Sci. A. Scopus Google Scholar). of CH25H protein in cells and macrophages can be by Cholesterol 25-hydroxylase production by cells and macrophages is by type I Biol. PubMed Scopus Google Scholar). has to of CH25H as of the genes and 25-HC as a of Li G. J.K. inhibits by production of 2013; Full Text Full Text PDF PubMed Scopus Google M. G. P. transcription macrophage of 25-hydroxycholesterol to the interferon 2013; Full Text Full Text PDF PubMed Scopus Google Scholar). 25-HC production is determined by CH25H that CH25H expression can 25-HC For of the and A production by 25-HC is substantially in mice CH25H expression (3.Reboldi A. Dang E.V. McDonald J.G. Liang G. Russell D.W. Cyster J.G. Inflammation. 25-Hydroxycholesterol suppresses interleukin-1-driven inflammation downstream of type I interferon.Science. 2014; 345: 679-684Crossref PubMed Scopus (297) Google McDonald J.G. Liang G. Russell D.W. 25-Hydroxycholesterol by macrophages in response to receptor activation suppresses A Natl. Acad. Sci. A. Scopus Google Scholar). CH25H expression can be activated by ligands and an manner M. G. P. transcription macrophage of 25-hydroxycholesterol to the interferon 2013; Full Text Full Text PDF PubMed Scopus Google Scholar). However, whether CH25H expression can be by other of mice with ligand induces CH25H expression in with the effect in the treatment also 25-HC which on CH25H expression McDonald J.G. Liang G. Russell D.W. 25-Hydroxycholesterol by macrophages in response to receptor activation suppresses A Natl. Acad. Sci. A. Scopus Google Scholar). that both macrophages and may be an important 25-HC we determined high CH25H expression in mouse liver and peritoneal macrophages in this a we identified several LXR response elements (LXREs) in the human CH25H promoter. the that 25-HC is an endogenous LXR ligand and that both LXR expression and oxysterol production can be in the cells with high cholesterol metabolism such as and we that 25-HC can activate CH25H expression in an LXR-dependent manner, which may be an important mechanism to exert the biological actions of 25-HC. 25-HC, and from Synthetic LXR GW3965 and from and from was from and from was from and HepG2 from and in complete and and macrophages and from mice and deficient mice as X. Z. X. Hajjar D.P. Han J. of and activation of liver X receptor induce macrophage ABCA1 expression and cholesterol Biol. Chem. Full Text Full Text PDF PubMed Scopus Google L. X. L. W. X. He J. D. the to hepatic in PubMed Scopus Google Scholar). with mice by the of and to the the and of by the of treatment in was from cells by as X. Chen M. Li X. Han J. induces the development of in mice by activating and PubMed Scopus Google Scholar). was and the and and and and CH25H mRNA expression was by or mRNA in the of and protein was determined by with cellular from HepG2 cells, hepatocytes, cells, peritoneal or mouse liver as X. M. L. Li G. Z. W. P. Activation of liver X receptor induces macrophage Biol. Chem. 2012; Full Text Full Text PDF PubMed Scopus Google Scholar). cells with and in an 1 1 and A of mouse liver was and in the or liver was at at with a was as the cellular or of an of protein from was on a the a was with a of 1 by with at with the was with or 1 at with the was 1 in a of of 1 and was to or to expression of or protein in HepG2 cells was determined by as L. Chen X. J. X. Li X. Li L. Hajjar D.P. activate macrophage ABCG1 expression and cholesterol function of PubMed Scopus Google Scholar). cells with with and with at with at cells with or at also with the a and the human LXRα and LXRβ into and expression of LXRα and LXRβ protein was by as X. M. L. Li G. Z. W. P. Activation of liver X receptor induces macrophage Biol. Chem. 2012; Full Text Full Text PDF PubMed Scopus Google Scholar). the human CH25H to was by with from HepG2 cells and the was into and the CH25H was with as in the in with and the the or HepG2 cells with or of of cells with the in the cellular was to and activity as X. Chen L. M. Li X. Hajjar D.P. of as a new target of liver X J. 2014; PubMed Scopus Google Scholar). activity in was as the of activity to activity in the and the activity of was further to the activity of the or the and the activity in the was as HepG2 cells LXRα or LXRβ expression protein J. the 2013; PubMed Scopus Google Scholar). was by the of the LXRα and LXRβ are and HepG2 cells with of or with of was the J. the 2013; PubMed Scopus Google Scholar), and the deletion of target expression was by cells LXRα and LXRβ expression as and cells, and the cells as further the role of in the cells with LXRβ by T317 against LXRβ was from of in the human CH25H with LXRα or LXRβ protein was determined by HepG2 cells with 25-HC or T317 by of X. Chen L. M. Li X. Hajjar D.P. of as a new target of liver X J. 2014; PubMed Scopus Google Scholar). was with from the of the was with the of from on the and or a or a negative was with the as E. A the of the in a receptor Mol. Biol. PubMed Scopus Google and the are in the of HepG2 cells in with T317 or 25-HC cellular and by of cholesterol and and by cellular protein W. W. Chen U. Z. J. receptor deficiency increases liver X receptor nuclear and hepatic lipogenesis through an protein PubMed Scopus Google Scholar). mice and deficient mice from the of and the the study was by the of from or mice by a the the was and the was with an liver was with 1 I and and at liver was through a by with at with and in density is of the was which was determined by the whether LXR activation can induce CH25H expression in mouse liver and peritoneal mice into and the treatment mice GW3965 mice GW3965, a synthetic LXR at a of the of mice and peritoneal and liver was to A of liver was to or hepatic lipid was determined by of liver and with the liver lipid as X. L. M. X. W. Li X. W. of and activation of LXR reduce atherosclerotic in Biol. PubMed Scopus Google Scholar). cellular protein and from a of liver or peritoneal macrophages by of CH25H protein and mRNA expression by and at and the are as and by a was 25-HC is produced from cholesterol in the by CH25H protein in may the of 25-HC We cellular from mouse and peritoneal macrophages and determined CH25H protein expression by in CH25H protein is expressed in particularly in the Meanwhile, a high expression of CH25H protein was found in mouse peritoneal macrophages. In by a we determined that CH25H mRNA in mouse and found in peritoneal macrophages in liver or macrophages be of the CH25H expression as as 25-HC production in a we identified several in the of the human CH25H Thus, we that CH25H expression can be induced by LXR this is the 25-HC may also activate CH25H expression in an LXR-dependent manner, on the that 25-HC is an endogenous LXR this we HepG2 cells, a human hepatic with synthetic LXR ligands and and 25-HC at different in that hepatic CH25H protein expression was induced by GW3965, and 25-HC in a manner. study that LXR ligands induced hepatic CH25H expression a of with the by 25-HC. In the of CH25H expression by LXR ligands can treatment In addition to 25-HC, other oxysterols can also function as endogenous LXR ligands to activate expression of LXR target For instance, is a LXR ligand macrophage ABCA1 expression, its can also induce ABCA1 expression but to a (7.Zhou X. He W. Huang Z. Gotto Jr., A.M. Hajjar D.P. Han J. Genetic deletion of low density lipoprotein receptor impairs sterol-induced mouse macrophage ABCA1 expression. A new SREBP1-dependent mechanism.J. Biol. Chem. 2008; 283: 2129-2138Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar). In this study, we determined that both and induced CH25H expression, with a effect by Thus, of CH25H expression by oxysterols may on to activate further the of hepatic CH25H protein expression by LXR we an study with intact HepG2 cells treatment with 25-HC and to the found from our that 25-HC or T317 substantially increased CH25H protein expression in HepG2 In by a study with and protein a of or a of we determined that CH25H with protein but not the protein that CH25H is an that activation of LXR by T317 and 25-HC can induce CH25H protein expression. whether the of CH25H protein at a level, we HepG2 cells with to protein in the or of T317 or 25-HC. We determined the of CH25H protein by in cellular CH25H protein to with of Meanwhile, addition of T317 to did not the of CH25H protein In contrast, the of cells with and 25-HC a in the of CH25H protein both and regulation of CH25H expression by LXR activation further LXR CH25H we the effect of LXR activation on CH25H mRNA expression. in and both 25-HC and T317 increased CH25H mRNA in both and the effect of LXR activation on CH25H we a CH25H and found that activity of the CH25H was increased by T317 or 25-HC treatment and that high-expressing LXRα or LXRβ also induced CH25H activity a we found in the of the human CH25H is also as a the on which are by are We found that of on are in the which is other that be the the role of in CH25H we several CH25H with a of and a with of the are in the in We determined that the CH25H was activated by 25-HC and the high-expressing Meanwhile, we found that the in CH25H with in the at the In we determined that the with the in a was activated by LXR the of the and to this CH25H by LXR activation other we determined that the of activity and the CH25H is activated by LXR activation further that is important CH25H transcription induced by LXR we a to the of with LXRα/β In addition to or we as a negative and as a of an in the CH25H promoter. the level, with the of the protein with the of LXRα or LXRβ protein with was in the However, treatment of cells with 25-HC or T317 increased the of LXRα or LXRβ protein to and whether the of CH25H expression by T317 or 25-HC is by we HepG2 cells with an LXRα or LXRβ expression and the cells with 25-HC. that high-expressing LXRα or LXRβ induced CH25H expression, and the was further enhanced by 25-HC we an LXRα or LXRβ HepG2 by the J. the 2013; PubMed Scopus Google Scholar), and as or deletion of LXRα or LXRβ protein expression in cells was by in both CH25H protein and mRNA expression activated by T317 and 25-HC in the However, the activation of CH25H protein expression was in cells LXRα or LXRβ expression activation of CH25H mRNA expression by T317 or 25-HC was in or cells that LXRα or LXRβ can induce CH25H expression. our we to whether LXR ligands can CH25H expression in cells with inhibition of both LXRα and LXRβ expression. cells with LXRβ by T317 with the T317-induced CH25H expression, which was associated with increased LXRβ expression in cells T317 activated CH25H expression in cells with LXRβ Taken together, the in that CH25H expression can be activated by 25-HC or T317 in an LXR-dependent manner. Activation of LXR has been demonstrated to play an important role in lipid metabolism. For instance, LXRα induces lipogenesis by activating which enhances FASN expression (9.Grefhorst A. Elzinga of lipogenesis by activation of the liver X receptor to production of low density lipoprotein Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). In to activation of LXR and expression, 25-HC SREBP2 to inhibit expression and cholesterol biosynthesis (2.Adams C.M. Reitz J. De Brabander J.K. Feramisco J.D. Li L. Brown M.S. Goldstein J.L. Cholesterol and 25-hydroxycholesterol inhibit activation of SREBPs by different mechanisms, both involving SCAP and Insigs.J. Biol. Chem. 2004; 279: 52772-52780Abstract Full Text Full Text PDF PubMed Scopus (340) Google Scholar). In this study, we determined the effect of 25-HC or T317 on cholesterol and biosynthesis in HepG2 treatment with T317 or 25-HC we found that both T317 and 25-HC SREBP2 by the of SREBP2 and expression was by both T317 and 25-HC with inhibition of expression, we found that cellular cholesterol Meanwhile, we that T317 and 25-HC expression of SREBP-1 and FASN T317 substantially induced SREBP-1 and FASN expression, 25-HC a effect on both a cellular increased by but not by 25-HC Activation of LXR can induce ABCA1 and ABCG1 expression to enhance cellular cholesterol We also determined that both T317 and 25-HC increased ABCA1 and ABCG1 in HepG2 cells which may be mechanism to the of cellular cholesterol in response to T317 or 25-HC treatment of CH25H has been to be induced in or macrophages. We that is an LXR target X. Chen L. M. Li X. Hajjar D.P. of as a new target of liver X J. 2014; PubMed Scopus Google Scholar). Thus, we that be in CH25H expression. this we from and and cells with 25-HC or We found that deficiency of expression CH25H expression at in cells, the of in CH25H expression. However, expression of CH25H was activated by 25-HC or T317 in cells In we determined that 25-HC or T317 induced CH25H expression in a manner in from or mice Taken together, the in that is important CH25H expression, but the of CH25H expression by T317 or 25-HC in an manner. have demonstrated that macrophage CH25H is an Li G. J.K. inhibits by production of 2013; Full Text Full Text PDF PubMed Scopus Google M. G. P. transcription macrophage of 25-hydroxycholesterol to the interferon 2013; Full Text Full Text PDF PubMed Scopus Google Scholar). macrophage is a type such as in this study that the macrophage is type that highly CH25H we the to whether activation of LXR can also induce macrophage CH25H protein expression. to hepatocytes, we determined that 25-HC, or GW3965 induced CH25H protein expression in a manner and the in peritoneal macrophages from In the macrophage we also that CH25H protein expression was activated by GW3965, or 25-HC in both and the we from the with mouse and HepG2 cells we can a that of CH25H expression by LXR activation can be of type or whether activation of LXR can induce CH25H expression in vivo, particularly in and we mice or GW3965 at a of 1 we mouse and peritoneal macrophage to our in vitro we found that expression of CH25H mRNA in liver and macrophages was increased by GW3965 with increased CH25H mRNA expression, CH25H protein expression in liver or macrophages was also by GW3965 treatment Activation of LXR can induce hepatic lipogenesis and to (6.Joseph S.B. McKilligin E. Pei L. Watson M.A. Collins A.R. Laffitte B.A. Chen M. Noh G. Goodman J. Hagger G.N. Synthetic LXR ligand inhibits the development of atherosclerosis in mice.Proc. Natl. Acad. Sci. USA. 2002; 99: 7604-7609Crossref PubMed Scopus (775) Google Scholar), in this study, we also determined that 1 of GW3965 in both and liver increased Meanwhile, hepatic lipid accumulation induced by GW3965 was by of liver 25-HC has as an important in different biological by as a negative regulator of activity and cholesterol a of and a of 25-HC can be from cholesterol by Although a of 25-HC can be found in cholesterol a of is to 25-HC in such as in vitro A. E. U. of oxysterol formation in vitro of low density 1995; PubMed Scopus Google Scholar). However, is possible to 25-HC as a in a For instance, 25-HC can be produced in the by cytochrome P450 and the enzymes production of and U. Russell D.W. in the Biol. Chem. Full Text PDF PubMed Google Russell D.W. of cholesterol a of cholesterol in the Natl. Acad. Sci. USA. PubMed Scopus Google A. J. Cholesterol activity of Full Text Full Text PDF PubMed Scopus Google Scholar). However, whether enzymes can 25-HC in CH25H not to the cytochrome P450 in the the role of CH25H in the production and actions of 25-HC in CH25H can be by in a manner. with of 25-HC in can be determined in U. A.M. M. U. of cholesterol 25-hydroxylase expression by Full Text Full Text PDF PubMed Scopus Google Scholar). of in activated macrophages from CH25H deficient mice can be to by 25-HC treatment (3.Reboldi A. Dang E.V. McDonald J.G. Liang G. Russell D.W. Cyster J.G. Inflammation. 25-Hydroxycholesterol suppresses interleukin-1-driven inflammation downstream of type I interferon.Science. 2014; 345: 679-684Crossref PubMed Scopus (297) Google Scholar). activation induces A production in cells CH25H expression. However, the is by extracellular 25-HC, that CH25H expression is critical the production and actions of 25-HC McDonald J.G. Liang G. Russell D.W. 25-Hydroxycholesterol by macrophages in response to receptor activation suppresses A Natl. Acad. Sci. A. Scopus Google Scholar). In this study, we demonstrated that the activated CH25H protein is in the which may be to the of its 25-HC, in the regulation of cholesterol biosynthesis. In the 25-HC enhances the of SCAP to thereby the of the to the and inhibiting expression (2.Adams C.M. Reitz J. De Brabander J.K. Feramisco J.D. Li L. Brown M.S. Goldstein J.L. Cholesterol and 25-hydroxycholesterol inhibit activation of SREBPs by different mechanisms, both involving SCAP and Insigs.J. Biol. Chem. 2004; 279: 52772-52780Abstract Full Text Full Text PDF PubMed Scopus (340) Google Scholar). of CH25H expression in the particularly in has been can macrophage CH25H mRNA expression and 25-HC production in a manner U. A.M. M. U. of cholesterol 25-hydroxylase expression by Full Text Full Text PDF PubMed Scopus Google Scholar). Activation of by A and activation of other by the ligands by from and by can also activate macrophage CH25H expression E.S. Podolsky I. R.L. Aderem A. 25-Hydroxycholesterol as an of Natl. Acad. Sci. USA. 2014; PubMed Scopus Google McDonald J.G. Liang G. Russell D.W. 25-Hydroxycholesterol by macrophages in response to receptor activation suppresses A Natl. Acad. Sci. A. Scopus Google Scholar). of macrophages or cells with or CH25H expression in a manner Cholesterol 25-hydroxylase production by cells and macrophages is by type I Biol. PubMed Scopus Google M. G. P. transcription macrophage of 25-hydroxycholesterol to the interferon 2013; Full Text Full Text PDF PubMed Scopus Google Scholar). Taken together, that CH25H expression in the can be by administration of A can activate CH25H expression in mouse with the effect on the liver McDonald J.G. Liang G. Russell D.W. 25-Hydroxycholesterol by macrophages in response to receptor activation suppresses A Natl. Acad. Sci. A. Scopus Google Scholar), that CH25H can be expressed by different and CH25H expression can be by different in this study, we that activation of LXR by 25-HC and synthetic LXR ligands increased CH25H expression in both and macrophages in vivo, we determined that administration of GW3965 to mice increased CH25H expression in both liver and peritoneal macrophages of macrophage CH25H can be induced by we identified that is an LXR target X. Chen L. M. Li X. Hajjar D.P. of as a new target of liver X J. 2014; PubMed Scopus Google Scholar). Activation of LXR by ligands induces expression and X. Chen L. M. Li X. Hajjar D.P. of as a new target of liver X J. 2014; PubMed Scopus Google X. Chen L. M. Li X. Han J. of by is associated with of J. PubMed Scopus Google Scholar). the CH25H expression may be by activation of we found that of expression the of CH25H the of in the activation of CH25H expression. However, LXR activation induced CH25H expression in cells expression Thus, we that can enhance but not CH25H expression. also the 25-HC and which may that LXR has different to CH25H expression in a manner. For instance, in cells highly such as LXR activation can induce CH25H expression in by activation of in and by activation of However, in cells with high cholesterol activity that have expression, the may the of LXR on CH25H expression. In on the that 25-HC is an endogenous LXR we identified in the CH25H and determined that activation of LXR by ligands including 25-HC can induce CH25H expression at the In we determined that of CH25H expression by LXR activation is of and expression. of CH25H expression can in vivo in response to LXR ligand We that the in this study our of the regulation of CH25H expression as as 25-HC biological acetyl-CoA carboxylase 1 protein cholesterol 25-hydroxylase HMG-CoA reductase 25-hydroxycholesterol liver X receptor LXR response protein receptor T0901317