Advertisement

The Orphan Nuclear Receptor LRH-1 Potentiates the Sterol-mediated Induction of the Human CETP Gene by Liver X Receptor*210

  • Yi Luo
    Correspondence
    To whom correspondence should be addressed:
    Affiliations
    From the Division of Molecular Medicine, Department of Medicine, Columbia University, New York, New York 10032
    Search for articles by this author
  • Chien-ping Liang
    Affiliations
    From the Division of Molecular Medicine, Department of Medicine, Columbia University, New York, New York 10032
    Search for articles by this author
  • Alan R. Tall
    Affiliations
    From the Division of Molecular Medicine, Department of Medicine, Columbia University, New York, New York 10032
    Search for articles by this author
  • Author Footnotes
    * The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
    210 The on-line version of this article (available athttp://www.jbc.org) contains Supplemental Table 1 and Figs.1 and 2.
Open AccessPublished:January 01, 2001DOI:https://doi.org/10.1074/jbc.M100912200
      The human cholesteryl ester transfer protein (CETP) transfers cholesteryl esters from high density lipoproteins to triglyceride-rich lipoproteins, indirectly facilitating cholesteryl esters uptake by the liver. Hepatic CETP gene expression is increased in response to dietary hypercholesterolemia, an effect that is mediated by the activity of liver X receptor/retinoid X receptor (LXR/RXR) on a direct repeat 4 element in the CETPpromoter. In this study we show that the orphan nuclear receptor LRH-1 also transactivates the CETP promoter by binding to a proximal promoter element distinct from the DR4 site. LRH-1 potentiates the sterol-dependent regulation of the wild typeCETP promoter by LXR/RXR. Small heterodimer partner, a repressor of LRH-1, abolishes the potentiation effect of LRH-1 but not its basal transactivation of the CETP promoter. Since this mode of regulation of CETP is very similar to that recently reported for the bile salt-mediated repression of Cyp7a(encoding the rate-limiting enzyme for conversion of cholesterol into bile acid in the liver), we examined the effects of bile salt feeding on CETP mRNA expression in human CETPtransgenic mice. Hepatic CETP mRNA expression was repressed by a diet containing 1% cholic acid in male mice but was induced by the same diet in female mice. Microarray analysis of hepatic mRNA showed that about 1.5% of genes were repressed, and 2.5% were induced by the bile acid diet. However, the sexually dimorphic regulatory pattern of the CETP gene was an unusual response. Our data provide further evidence for the regulation ofCETP and Cyp7a genes by similar molecular mechanisms, consistent with coordinate transcriptional regulation of sequential steps of reverse cholesterol transport. However, differential effects of the bile salt diet indicate additional complexity in the response of these two genes.
      CETP
      cholesteryl ester transfer protein
      HDL
      high density lipoproteins
      NFR
      native flanking region
      CA
      cholic acid
      LRH
      liver receptor homologue
      LRHBS
      LRH-binding site
      kb
      kilobase pair
      FXR
      farnesoid X receptor
      LXR
      liver X receptor
      RXR
      retinoid X receptor
      CPF
      CYP7A promoter binding factor
      SHP-1
      small heterodimer partner 1
      kb
      kilobase pair
      LRHE
      LRH element
      TNFα
      tumor necrosis factor α
      EST
      expressed sequence tag
      SHP
      small heterodimer partner
      The cholesteryl ester transfer protein (CETP)1 catalyzes the transfer of cholesterol ester from HDL to triglyceride-rich lipoproteins (
      • Tall A.
      ). CETP is expressed in liver, intestine, and a number of peripheral tissues, such as adipose (
      • Tall A.
      ). In humans and animals, plasma CETP and tissue mRNA levels are increased in response to high fat, high cholesterol diets or endogenous hypercholesterolemia. These increases are due to elevated CETP gene transcription especially in the liver (
      • Quinet E.M.
      • Agellon L.B.
      • Kroon P.A.
      • Marcel Y.L.
      • Lee Y.C.
      • Whitlock M.E.
      • Tall A.R.
      ,
      • Masucci-Magoulas L.
      • Plump A.
      • Jiang X.C.
      • Walsh A.
      • Breslow J.L.
      • Tall A.R.
      ). Transgenic mice expressing human CETP, controlled by its natural flanking region, also increase expression of CETP in response to hypercholesterolemia (
      • Jiang X.C.
      • Agellon L.B.
      • Walsh A.
      • Breslow J.L.
      • Tall A.
      ). The mechanism of this effect was recently shown to involve the transcription factor LXR, binding as a heterodimer with RXR to a site in the CETPproximal promoter, a direct repeat of a nuclear receptor binding sequence separated by 4 nucleotides (DR4 element, −384 to −399). This response was seen with both LXRα and LXRβ, related nuclear hormone receptors that bind and are activated by specific hydroxylated sterols at physiological concentrations (
      • Janowski B.A.
      • Willy P.J.
      • Devi T.R.
      • Falck J.R.
      • Mangelsdorf D.J.
      ,
      • Janowski B.A.
      • Grogan M.J.
      • Jones S.A.
      • Wisely G.B.
      • Kliewer S.A.
      • Corey E.J.
      • Mangelsdorf D.J.
      ).
      LXRα also transactivates the Cyp7a gene, encoding cholesterol 7α-hydroxylase, the rate-limiting enzyme in the pathway converting cholesterol to bile acids (
      • Lehmann J.M.
      • Kliewer S.A.
      • Moore L.B.
      • Smith-Oliver T.A.
      • Oliver B.B.
      • Su J.L.
      • Sundseth S.S.
      • Winegar D.A.
      • Blanchard D.E.
      • Spencer T.A.
      • Willson T.M.
      ). Furthermore, disruption ofLXRα in mice abolished the induction of Cyp7aexpression by dietary cholesterol (
      • Peet D.J.
      • Turley S.D.
      • Ma W.
      • Janowski B.A.
      • Lobaccaro J.M.
      • Hammer R.E.
      • Mangelsdorf D.J.
      ). Based on these data, we proposed that LXRs may coordinate the regulation of genes involved in different steps of reverse cholesterol transport (
      • Luo Y.
      • Tall A.R.
      ). This idea was further supported by the demonstration that ABCA1 is up-regulated by sterols in an LXR-dependent fashion, due to the interaction of LXR with a DR4 element in the proximal promoter of theABCA1 gene (
      • Costet P.
      • Luo Y.
      • Wang N.
      • Tall A.R.
      ). ABCA1, the gene that is mutated in Tangier disease, mediates phospholipid and cholesterol efflux from macrophages to apoA-I (
      • Marcil M.
      • Brooks-Wilson A.
      • Clee S.M.
      • Roomp K.
      • Zhang L.H., Yu, L.
      • Collins J.A.
      • van Dam M.
      • Molhuizen H.O.
      • Loubster O.
      • Ouellette B.F.
      • Sensen C.W.
      • Fichter K.
      • Mott S.
      • Denis M.
      • Boucher B.
      • Pimstone S.
      • Genest Jr., J.
      • Kastelein J.J.
      • Hayden M.R.
      ,
      • Bodzioch M.
      • Orso E.
      • Klucken J.
      • Langmann T.
      • Bottcher A.
      • Diederich W.
      • Drobnik W.
      • Barlage S.
      • Buchler C.
      • Porsch-Ozcurumez M.
      • Kaminski W.E.
      • Hahmann H.W.
      • Oette K.
      • Rothe G.
      • Aslanidis C.
      • Lackner K.J.
      • Schmitz G.
      ,
      • Brooks-Wilson A.
      • Marcil M.
      • Clee S.M.
      • Zhang L.H.
      • Roomp K.
      • van Dam M., Yu, L.
      • Brewer C.
      • Collins J.A.
      • Molhuizen H.O.
      • Loubser O.
      • Ouelette B.F.
      • Fichter K.
      • Ashbourne-Excoffon K.J.
      • Sensen C.W.
      • Scherer S.
      • Mott S.
      • Denis M.
      • Martindale D.
      • Frohlich J.
      • Morgan K.
      • Koop B.
      • Pimstone S.
      • Kastelein J.J.
      • Hayden M.R.
      ,
      • Orso E.
      • Broccardo C.
      • Kaminski W.E.
      • Bottcher A.
      • Liebisch G.
      • Drobnik W.
      • Gotz A.
      • Chambenoit O.
      • Diederich W.
      • Langmann T.
      • Spruss T.
      • Luciani M.F.
      • Rothe G.
      • Lackner K.J.
      • Chimini G.
      • Schmitz G.
      ,
      • Wang N.
      • Silver D.L.
      • Costet P.
      • Tall A.R.
      ). Recently, additional LXR-regulated ABC transporters were shown to be mutated in sitosterolemia, implying a role for these molecules in excretion of sitosterol and cholesterol from intestinal cells (
      • Berge K.E.
      • Tian H.
      • Graf G.A., Yu, L.
      • Grishin N.V.
      • Schultz J.
      • Kwiterovich P.
      • Shan B.
      • Barnes R.
      • Hobbs H.H.
      ). In addition to stimulating reverse cholesterol transport and cholesterol excretion, LXRs activate the promoter of SREBP-1c, indicating a role in the regulation of fatty acid synthesis (
      • Repa J.J.
      • Liang G.
      • Ou J.
      • Bashmakov Y.
      • Lobaccaro J.M.
      • Shimomura I.
      • Shan B.
      • Brown M.S.
      • Goldstein J.L.
      • Mangelsdorf D.J.
      ,
      • Schultz J.R.
      • Tu H.
      • Luk A.
      • Repa J.J.
      • Medina J.C.
      • Li L.
      • Schwendner S.
      • Wang S.
      • Thoolen M.
      • Mangelsdorf D.J.
      • Lustig K.D.
      • Shan B.
      ).
      Liver receptor homologue-1 (LRH-1) is a mouse homologue of the orphan nuclear receptor fushi tarazu F1 (Ftz-F1) from Drosophila. CYP7A promoter binding factor (CPF), the human homologue of LRH-1, was found to transactivate the human CYP7A promoter (
      • Nitta M.
      • Ku S.
      • Brown C.
      • Okamoto A.Y.
      • Shan B.
      ). LRH-1 and CPF bind to an extended nuclear hormone receptor-binding site as monomers. LRH-1 has also been shown to act as a competence factor, enhancing the ability of LXRα/RXRα to mediate a sterol response on the Cyp7a gene (
      • Lu T.T.
      • Makishima M.
      • Repa J.J.
      • Schoonjans K.
      • Kerr T.A.
      • Auwerx J.
      • Mangelsdorf D.J.
      ). This interaction is abolished by small heterodimer partner 1 (SHP-1), just as SHP-1 negates the interaction of DAX1 with SF-1 (
      • Parker K.L.
      • Schedl A.
      • Schimmer B.P.
      ) and represses the activity of several nuclear receptors (
      • Seol W.
      • Choi H.S.
      • Moore D.D.
      ,
      • Seol W.
      • Hanstein B.
      • Brown M.
      • Moore D.D.
      ,
      • Lee Y.K.
      • Dell H.
      • Dowhan D.H.
      • Hadzopoulou-Cladaras M.
      • Moore D.D.
      ). Since CETP and Cyp7a are both regulated by LXR/RXR, we investigated the role of LRH-1 and SHP-1 in the regulation of CETP gene expression. Our study shows a marked similarity between the effects of these factors on theCETP and Cyp7a promoters. This supports the idea of coordinate regulation of the sequential metabolic steps mediated by CETP and CYP7A. However, divergent responses of these two genes to a cholic acid-containing diet indicate additional complexity in thein vivo response to bile acids.

      DISCUSSION

      We have shown that the orphan nuclear receptor LRH-1 binds and transactivates the human CETP promoter. In 293 cells, the native CETP promoter showed modest sterol induction in the presence of LXRα/RXRα or LXRβ/RXRα (Fig. 1 and Supplemental Fig. 2). The expression of LRH-1 enhanced the response of LXR/RXR to sterols. The principal tissue expressing LRH-1 is the liver, which also is a major site where CETP is expressed (
      • Jiang X.C.
      • Agellon L.B.
      • Walsh A.
      • Breslow J.L.
      • Tall A.
      ). Even though CETP is expressed in peripheral tissues, the sterol regulation in peripheral tissue is less pronounced than in liver (
      • Jiang X.C.
      • Agellon L.B.
      • Walsh A.
      • Breslow J.L.
      • Tall A.
      ). A requirement for LRH-1 in the sterol induction mediated by LXR might confer tissue specificity for the induction of genes by sterols, since the ubiquitously expressed LXRβ could otherwise mediate sterol induction of CETPgene. Additional physiological significance might be that LRH-1 abolishes the requirement for RXR ligands, such as 9-cis-retinoic acid or docosahexanoic acid (
      • de Urquiza A.M.
      • Liu S.
      • Sjoberg M.
      • Zetterstrom R.H.
      • Griffiths W.
      • Sjovall J.
      • Perlmann T.
      ), in order to obtain significant LXR-mediated sterol induction of gene expression. Thus, in response to endogenous hypercholesterolemia, 24(S),25-epoxycholesterol, which is synthesized from a shunt pathway (
      • Nelson J.A.
      • Steckbeck S.R.
      • Spencer T.A.
      ) and has been shown to act as an LXR ligand (
      • Janowski B.A.
      • Grogan M.J.
      • Jones S.A.
      • Wisely G.B.
      • Kliewer S.A.
      • Corey E.J.
      • Mangelsdorf D.J.
      ), may bind and activate LXR/RXR without the requirement for additional RXR ligands. This effect is clearly shown in Fig. 8 and Supplemental Fig. 2. The presence of LRH increased the induction of CETP by sterol but had no additional incremental effect as a result of the addition of 9-cis-retinoic acid.
      The effect of LRH-1 was strikingly specific for the LXR-dependent sterol induction of CETPexpression. The mechanism of the LRH-1 potentiation effect required the binding of LRH-1 to a site (−75 to −83) (LRHBS) on theCETP promoter, and the DNA binding ability is required for the potentiation function of LRH-1, since mutation of the LRH-1 DNA-binding zinc finger motif abolished this effect (not shown). The activity of LRH-1 on the CETP promoter might enhance ligand binding to LXR or cooperatively work with LXR/RXR to recruit ligand-dependent co-activators. The co-activator SRC-1 (nuclear receptor co-activator) has been shown to interact with LXRβ/RXR upon binding of 22(R)-hydroxycholesterol and/or 9-cis-retinoic acid (
      • Wiebel F.F.
      • Steffensen K.R.
      • Treuter E.
      • Feltkamp D.
      • Gustafsson J.A.
      ). It is possible that sterol-dependent binding of co-activator is enhanced either by the LRH/LXR activation or by retinoid binding to RXR. This would explain why in the presence of sterols the expression of LRH or activation by 9-cis-retinoic acid achieved similar promoter activity (Fig. 8).
      Recently, considerable evidence has been obtained to support the idea that LXR/RXR coordinates the regulation of genes involved in reverse cholesterol transport (
      • Luo Y.
      • Tall A.R.
      ), such as ABCA1 (
      • Costet P.
      • Luo Y.
      • Wang N.
      • Tall A.R.
      ,
      • Repa J.J.
      • Turley S.D.
      • Lobaccaro J.A.
      • Medina J.
      • Li L.
      • Lustig K.
      • Shan B.
      • Heyman R.A.
      • Dietschy J.M.
      • Mangelsdorf D.J.
      ),CETP (
      • Luo Y.
      • Tall A.R.
      ), Cyp7a (
      • Lehmann J.M.
      • Kliewer S.A.
      • Moore L.B.
      • Smith-Oliver T.A.
      • Oliver B.B.
      • Su J.L.
      • Sundseth S.S.
      • Winegar D.A.
      • Blanchard D.E.
      • Spencer T.A.
      • Willson T.M.
      ,
      • Peet D.J.
      • Turley S.D.
      • Ma W.
      • Janowski B.A.
      • Lobaccaro J.M.
      • Hammer R.E.
      • Mangelsdorf D.J.
      ), and apoE (
      • Laffitte B.A.
      • Repa J.J.
      • Joseph S.B.
      • Wilpitz D.C.
      • Kast H.R.
      • Mangelsdorf D.J.
      • Tontonoz P.
      ). It appears that ABCA1 does not need LRH-1 as a competence factor for the regulation by LXR/RXR, since the LXR/RXR-binding site is sufficient to mediate sterol induction in cultured cells in the context of the native promoter (
      • Costet P.
      • Luo Y.
      • Wang N.
      • Tall A.R.
      ). ApoE and ABC1 are involved in the initial step of cholesterol efflux from macrophage foam cells, resulting in enrichment of HDL particles with cholesterol and cholesteryl ester. CETP transfers cholesteryl esters between lipoproteins in the bloodstream, and thereby facilitates the transport of HDL cholesterol ester into the liver. Cyp7a converts cholesterol into bile acids in the liver, leading to excretion from the body.
      The mechanism of regulation of CETP by LXR/RXR and LRH is strikingly similar to the regulation of Cyp7a by these factors. The sterol induction of Cyp7a has also been shown to require LRH-1 as a potentiation or competence factor (
      • Lu T.T.
      • Makishima M.
      • Repa J.J.
      • Schoonjans K.
      • Kerr T.A.
      • Auwerx J.
      • Mangelsdorf D.J.
      ). The competence effect requires binding of LRH-1 to both CETP andCyp7a promoters. Similar to its effects on the humanCETP promoter, LRH-1 (CPF) transactivates the humanCYP7A promoter in 293 cells (
      • Nitta M.
      • Ku S.
      • Brown C.
      • Okamoto A.Y.
      • Shan B.
      ). However, little basal transactivation of the rat Cyp7a promoter by LRH-1 was seen in 293 cells (
      • Lu T.T.
      • Makishima M.
      • Repa J.J.
      • Schoonjans K.
      • Kerr T.A.
      • Auwerx J.
      • Mangelsdorf D.J.
      ). In the rat Cyp7a promoter, LRH-1 not only increased the induction by sterol but also the additive or synergistic induction by both sterols and 9-cis-retinoic acid. However, in the CETP promoter, LRH-1 only increased the induction by sterol. These results imply that the competence mechanism of LRH-1 onCETP and Cyp7a might be slightly different.
      Cyp7a is not only regulated by hydroxysterols, but also is under feedback control by bile salts in the entero-hepatic circulation. The nuclear receptor FXR was recently identified as a receptor for the bile acid, chenodeoxycholic acid (
      • Makishima M.
      • Okamoto A.Y.
      • Repa J.J.
      • Tu H.
      • Learned R.M.
      • Luk A.
      • Hull M.V.
      • Lustig K.D.
      • Mangelsdorf D.J.
      • Shan B.
      ,
      • Parks D.J.
      • Blanchard S.G.
      • Bledsoe R.K.
      • Chandra G.
      • Consler T.G.
      • Kliewer S.A.
      • Stimmel J.B.
      • Willson T.M.
      • Zavacki A.M.
      • Moore D.D.
      • Lehmann J.M.
      ,
      • Wang H.
      • Chen J.
      • Hollister K.
      • Sowers L.C.
      • Forman B.M.
      ). Binding of FXR to the promoters of several bile salt-induced genes, such as ileal bile acid-binding protein and phospholipid transfer protein, resulted in bile acid-dependent promoter activation (
      • Makishima M.
      • Okamoto A.Y.
      • Repa J.J.
      • Tu H.
      • Learned R.M.
      • Luk A.
      • Hull M.V.
      • Lustig K.D.
      • Mangelsdorf D.J.
      • Shan B.
      ,
      • Laffitte B.A.
      • Kast H.R.
      • Nguyen C.M.
      • Zavacki A.M.
      • Moore D.D.
      • Edwards P.A.
      ). It has been suggested that FXR/RXR may also mediate the bile acid repression of Cyp7a; however, since FXR/RXR does not bind the bile acid response element in the Cyp7a promoter, an indirect mechanism is implied (
      • Chiang J.Y.
      • Kimmel R.
      • Weinberger C.
      • Stroup D.
      ). Disruption of FXR has provided strong evidence for a role of FXR in up-regulating expression of genes such as the ileal bile acid transporter and the basal bile salt exporter (
      • Sinal C.J.
      • Tohkin M.
      • Miyata M.
      • Ward J.M.
      • Lambert G.
      • Gonzalez F.J.
      ). FXR knock-out mice also failed to repress hepatic Cyp7a mRNA levels in response to a cholic acid-containing diet (
      • Sinal C.J.
      • Tohkin M.
      • Miyata M.
      • Ward J.M.
      • Lambert G.
      • Gonzalez F.J.
      ), suggesting a role for this factor in bile salt-mediated gene repression.
      Recently, it has been proposed that FXR induces SHP, which then interacts with LRH-1, preventing its activation of the Cyp7apromoter (
      • Lu T.T.
      • Makishima M.
      • Repa J.J.
      • Schoonjans K.
      • Kerr T.A.
      • Auwerx J.
      • Mangelsdorf D.J.
      ,
      • Goodwin B.
      • Jones S.A.
      • Price R.R.
      • Watson M.A.
      • McKee D.D.
      • Moore L.B.
      • Galardi C.
      • Wilson J.G.
      • Lewis M.C.
      • Roth M.E.
      • Maloney P.R.
      • Willson T.M.
      • Kliewer S.A.
      ). SHP, a transcriptional repressor, was induced by bile acid treatment as a result of activity of FXR/RXR on the SHP promoter; furthermore, SHP directly interacts with LRH-1 and represses LRH-1 activity in cell culture (
      • Lu T.T.
      • Makishima M.
      • Repa J.J.
      • Schoonjans K.
      • Kerr T.A.
      • Auwerx J.
      • Mangelsdorf D.J.
      ,
      • Goodwin B.
      • Jones S.A.
      • Price R.R.
      • Watson M.A.
      • McKee D.D.
      • Moore L.B.
      • Galardi C.
      • Wilson J.G.
      • Lewis M.C.
      • Roth M.E.
      • Maloney P.R.
      • Willson T.M.
      • Kliewer S.A.
      ). The abolition of LRH facilitation of the LXR-mediated sterol response by SHP was strikingly similar in the CETP and Cyp7a promoters (this study and (
      • Lu T.T.
      • Makishima M.
      • Repa J.J.
      • Schoonjans K.
      • Kerr T.A.
      • Auwerx J.
      • Mangelsdorf D.J.
      )). A weak or absent effect of SHP on basal promoter activity in the presence of LRH also appears to be similar for CETP and Cyp7a (
      • Lu T.T.
      • Makishima M.
      • Repa J.J.
      • Schoonjans K.
      • Kerr T.A.
      • Auwerx J.
      • Mangelsdorf D.J.
      ). However, in previous studies (
      • Jiang X.C.
      • Agellon L.B.
      • Walsh A.
      • Breslow J.L.
      • Tall A.
      ) we observed that a high fat, high cholesterol diet containing bile salts induced hepatic CETP mRNA expression, whereas Cyp7a mRNA is repressed in response to the same diet. In the present study a somewhat different response ofCETP and Cyp7a genes to a chow diet supplemented with 1% cholic acid was seen. Whereas Cyp7a mRNA was repressed by the bile salt-supplemented diet in both sexes,CETP mRNA was repressed in males but induced in female mice.
      In an attempt to understand these different responses, we characterized the responses of about 1200 different cDNAs and ESTs to the bile salt diet. The majority of differentially expressed genes were either induced or repressed in parallel fashion in both sexes. However, 11 genes gave a sexually dimorphic response, with the majority showing an induction in males but not in females. Thus, the CETPresponse is unusual and is unlikely to be mediated by a simple mechanism, such as induction of a single transcription factor in one sex but not the other. The array results provide an intriguing hint for how the differential response could be mediated. Thus, the TNFα-induced protein 2 was increased in males and decreased in females, suggesting that there could be a dimorphic effect of TNFα signaling in male versus female mice. Hepatic TNFα expression is induced by the cholic acid diet (it is probably made in Kupffer cells) (
      • Miyake J.H.
      • Wang S.L.
      • Davis R.A.
      ), and TNFα has been shown to repress bothCETP (
      • Hardardottir I.
      • Moser A.H.
      • Fuller J.
      • Fielding C.
      • Feingold K.
      • Grunfeld C.
      ) and Cyp7a (
      • Feingold K.R.
      • Spady D.K.
      • Pollock A.S.
      • Moser A.H.
      • Grunfeld C.
      ). If the effect of TNFα is larger in male mice, this could explain why CETP is repressed in this sex. One has to then hypothesize an additional factor that up-regulates CETP in response to bile acids and only becomes apparent in females because of a lessened TNFα effect. The related gene PLTP is up-regulated by the bile salt diet, through an FXR mechanism (
      • Laffitte B.A.
      • Kast H.R.
      • Nguyen C.M.
      • Zavacki A.M.
      • Moore D.D.
      • Edwards P.A.
      ), and it is conceivable thatCETP could be similarly regulated. Induction of TNFα and interleukin-1 by the bile salt diet has also been suggested as a possible mechanism of repression of Cyp7a (
      • Miyake J.H.
      • Wang S.L.
      • Davis R.A.
      ,
      • Urizar N.L.
      • Dowhan D.H.
      • Moore D.D.
      ), but this response was not dimorphic. There could be additional mechanisms of repression of Cyp7a, such as that proposed involving FXR, SHP, and LRH, affecting both sexes.
      In summary, we have shown that the competence factor, LRH, enhances the LXR-mediated sterol response of the CETP promoter, probably contributes to the moderate tissue specificity of this response (
      • Oliveira H.C.F.
      • Chouinard R.A.
      • Agellon L.B.
      • Bruce C.
      • Ma L.
      • Walsh A.
      • Breslow J.L.
      • Tall A.R.
      ), and provides a way for the CETP promoter to respond to sterols, independent of RXR agonists. Both of these effects,i.e. tissue-specific responses and responses to LXR/RXR that are independent of RXR ligands, may be general properties of competence factors in transcriptional responses. The interaction of LXR and LRH in the sterol-dependent induction of the CETP andCyp7a promoters, and the repression of this effect by SHP, is strikingly similar for CETP and Cyp7a, supporting the idea of coordinate regulation of these two genes in the liver (
      • Luo Y.
      • Tall A.R.
      ). However, the divergent responses of these and other genes to diets containing bile salts highlights the complexity of the in vivo response to this challenge.

      REFERENCES

        • Tall A.
        Annu. Rev. Biochem. 1995; 64: 235-257
        • Quinet E.M.
        • Agellon L.B.
        • Kroon P.A.
        • Marcel Y.L.
        • Lee Y.C.
        • Whitlock M.E.
        • Tall A.R.
        J. Clin. Invest. 1990; 85: 357-363
        • Masucci-Magoulas L.
        • Plump A.
        • Jiang X.C.
        • Walsh A.
        • Breslow J.L.
        • Tall A.R.
        J. Clin. Invest. 1996; 97: 154-161
        • Jiang X.C.
        • Agellon L.B.
        • Walsh A.
        • Breslow J.L.
        • Tall A.
        J. Clin. Invest. 1992; 90: 1290-1295
        • Janowski B.A.
        • Willy P.J.
        • Devi T.R.
        • Falck J.R.
        • Mangelsdorf D.J.
        Nature. 1996; 383: 728-731
        • Janowski B.A.
        • Grogan M.J.
        • Jones S.A.
        • Wisely G.B.
        • Kliewer S.A.
        • Corey E.J.
        • Mangelsdorf D.J.
        Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 266-271
        • Lehmann J.M.
        • Kliewer S.A.
        • Moore L.B.
        • Smith-Oliver T.A.
        • Oliver B.B.
        • Su J.L.
        • Sundseth S.S.
        • Winegar D.A.
        • Blanchard D.E.
        • Spencer T.A.
        • Willson T.M.
        J. Biol. Chem. 1997; 272: 3137-3140
        • Peet D.J.
        • Turley S.D.
        • Ma W.
        • Janowski B.A.
        • Lobaccaro J.M.
        • Hammer R.E.
        • Mangelsdorf D.J.
        Cell. 1998; 93: 693-704
        • Luo Y.
        • Tall A.R.
        J. Clin. Invest. 2000; 105: 513-520
        • Costet P.
        • Luo Y.
        • Wang N.
        • Tall A.R.
        J. Biol. Chem. 2000; 275: 28240-28245
        • Marcil M.
        • Brooks-Wilson A.
        • Clee S.M.
        • Roomp K.
        • Zhang L.H., Yu, L.
        • Collins J.A.
        • van Dam M.
        • Molhuizen H.O.
        • Loubster O.
        • Ouellette B.F.
        • Sensen C.W.
        • Fichter K.
        • Mott S.
        • Denis M.
        • Boucher B.
        • Pimstone S.
        • Genest Jr., J.
        • Kastelein J.J.
        • Hayden M.R.
        Lancet. 1999; 354: 1341-1346
        • Bodzioch M.
        • Orso E.
        • Klucken J.
        • Langmann T.
        • Bottcher A.
        • Diederich W.
        • Drobnik W.
        • Barlage S.
        • Buchler C.
        • Porsch-Ozcurumez M.
        • Kaminski W.E.
        • Hahmann H.W.
        • Oette K.
        • Rothe G.
        • Aslanidis C.
        • Lackner K.J.
        • Schmitz G.
        Nat. Genet. 1999; 22: 347-351
        • Brooks-Wilson A.
        • Marcil M.
        • Clee S.M.
        • Zhang L.H.
        • Roomp K.
        • van Dam M., Yu, L.
        • Brewer C.
        • Collins J.A.
        • Molhuizen H.O.
        • Loubser O.
        • Ouelette B.F.
        • Fichter K.
        • Ashbourne-Excoffon K.J.
        • Sensen C.W.
        • Scherer S.
        • Mott S.
        • Denis M.
        • Martindale D.
        • Frohlich J.
        • Morgan K.
        • Koop B.
        • Pimstone S.
        • Kastelein J.J.
        • Hayden M.R.
        Nat. Genet. 1999; 22: 336-345
        • Orso E.
        • Broccardo C.
        • Kaminski W.E.
        • Bottcher A.
        • Liebisch G.
        • Drobnik W.
        • Gotz A.
        • Chambenoit O.
        • Diederich W.
        • Langmann T.
        • Spruss T.
        • Luciani M.F.
        • Rothe G.
        • Lackner K.J.
        • Chimini G.
        • Schmitz G.
        Nat. Genet. 2000; 24: 192-196
        • Wang N.
        • Silver D.L.
        • Costet P.
        • Tall A.R.
        J. Biol. Chem. 2000; 275: 33053-33058
        • Berge K.E.
        • Tian H.
        • Graf G.A., Yu, L.
        • Grishin N.V.
        • Schultz J.
        • Kwiterovich P.
        • Shan B.
        • Barnes R.
        • Hobbs H.H.
        Science. 2000; 290: 1771-1775
        • Repa J.J.
        • Liang G.
        • Ou J.
        • Bashmakov Y.
        • Lobaccaro J.M.
        • Shimomura I.
        • Shan B.
        • Brown M.S.
        • Goldstein J.L.
        • Mangelsdorf D.J.
        Genes Dev. 2000; 14: 2819-2830
        • Schultz J.R.
        • Tu H.
        • Luk A.
        • Repa J.J.
        • Medina J.C.
        • Li L.
        • Schwendner S.
        • Wang S.
        • Thoolen M.
        • Mangelsdorf D.J.
        • Lustig K.D.
        • Shan B.
        Genes Dev. 2000; 14: 2831-2838
        • Nitta M.
        • Ku S.
        • Brown C.
        • Okamoto A.Y.
        • Shan B.
        Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 6660-6665
        • Lu T.T.
        • Makishima M.
        • Repa J.J.
        • Schoonjans K.
        • Kerr T.A.
        • Auwerx J.
        • Mangelsdorf D.J.
        Mol. Cell. 2000; 6: 507-515
        • Parker K.L.
        • Schedl A.
        • Schimmer B.P.
        Annu. Rev. Physiol. 1999; 61: 417-433
        • Seol W.
        • Choi H.S.
        • Moore D.D.
        Science. 1996; 272: 1336-1339
        • Seol W.
        • Hanstein B.
        • Brown M.
        • Moore D.D.
        Mol. Endocrinol. 1998; 12: 1551-1557
        • Lee Y.K.
        • Dell H.
        • Dowhan D.H.
        • Hadzopoulou-Cladaras M.
        • Moore D.D.
        Mol. Cell. Biol. 2000; 20: 187-195
        • Chouinard Jr., R.A.
        • Luo Y.
        • Osborne T.F.
        • Walsh A.
        • Tall A.R.
        J. Biol. Chem. 1998; 273: 22409-22414
        • Eisen M.B.
        • Brown P.O.
        Methods Enzymol. 1999; 303: 179-205
        • Goodwin B.
        • Jones S.A.
        • Price R.R.
        • Watson M.A.
        • McKee D.D.
        • Moore L.B.
        • Galardi C.
        • Wilson J.G.
        • Lewis M.C.
        • Roth M.E.
        • Maloney P.R.
        • Willson T.M.
        • Kliewer S.A.
        Mol. Cell. 2000; 6: 517-526
        • del Castillo-Olivares A.
        • Gil G.
        J. Biol. Chem. 2000; 275: 17793-17799
        • Sinal C.J.
        • Tohkin M.
        • Miyata M.
        • Ward J.M.
        • Lambert G.
        • Gonzalez F.J.
        Cell. 2000; 102: 731-744
        • Schena M.
        • Shalon D.
        • Davis R.W.
        • Brown P.O.
        Science. 1995; 270: 467-470
        • Acton S.
        • Rigotti A.
        • Landschulz K.T.
        • Xu S.
        • Hobbs H.H.
        • Krieger M.
        Science. 1996; 271: 518-520
        • Feingold K.R.
        • Spady D.K.
        • Pollock A.S.
        • Moser A.H.
        • Grunfeld C.
        J. Lipid Res. 1996; 37: 223-228
        • Miyake J.H.
        • Wang S.L.
        • Davis R.A.
        J. Biol. Chem. 2000; 275: 21805-21808
        • Hardardottir I.
        • Moser A.H.
        • Fuller J.
        • Fielding C.
        • Feingold K.
        • Grunfeld C.
        J. Clin. Invest. 1996; 97: 2585-2592
        • de Urquiza A.M.
        • Liu S.
        • Sjoberg M.
        • Zetterstrom R.H.
        • Griffiths W.
        • Sjovall J.
        • Perlmann T.
        Science. 2000; 290: 2140-2144
        • Nelson J.A.
        • Steckbeck S.R.
        • Spencer T.A.
        J. Biol. Chem. 1981; 256: 1067-1068
        • Wiebel F.F.
        • Steffensen K.R.
        • Treuter E.
        • Feltkamp D.
        • Gustafsson J.A.
        Mol. Endocrinol. 1999; 13: 1105-1118
        • Repa J.J.
        • Turley S.D.
        • Lobaccaro J.A.
        • Medina J.
        • Li L.
        • Lustig K.
        • Shan B.
        • Heyman R.A.
        • Dietschy J.M.
        • Mangelsdorf D.J.
        Science. 2000; 289: 1524-1529
        • Laffitte B.A.
        • Repa J.J.
        • Joseph S.B.
        • Wilpitz D.C.
        • Kast H.R.
        • Mangelsdorf D.J.
        • Tontonoz P.
        Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 507-512
        • Makishima M.
        • Okamoto A.Y.
        • Repa J.J.
        • Tu H.
        • Learned R.M.
        • Luk A.
        • Hull M.V.
        • Lustig K.D.
        • Mangelsdorf D.J.
        • Shan B.
        Science. 1999; 284: 1362-1365
        • Parks D.J.
        • Blanchard S.G.
        • Bledsoe R.K.
        • Chandra G.
        • Consler T.G.
        • Kliewer S.A.
        • Stimmel J.B.
        • Willson T.M.
        • Zavacki A.M.
        • Moore D.D.
        • Lehmann J.M.
        Science. 1999; 284: 1365-1368
        • Wang H.
        • Chen J.
        • Hollister K.
        • Sowers L.C.
        • Forman B.M.
        Mol. Cell. 1999; 3: 543-553
        • Laffitte B.A.
        • Kast H.R.
        • Nguyen C.M.
        • Zavacki A.M.
        • Moore D.D.
        • Edwards P.A.
        J. Biol. Chem. 2000; 275: 10638-10647
        • Chiang J.Y.
        • Kimmel R.
        • Weinberger C.
        • Stroup D.
        J. Biol. Chem. 2000; 275: 10918-10924
        • Urizar N.L.
        • Dowhan D.H.
        • Moore D.D.
        J. Biol. Chem. 2000; 275: 39313-39317
        • Oliveira H.C.F.
        • Chouinard R.A.
        • Agellon L.B.
        • Bruce C.
        • Ma L.
        • Walsh A.
        • Breslow J.L.
        • Tall A.R.
        J. Biol. Chem. 1996; 271: 31831-31838