HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 276, Issue 46, 43018-43024, November 16, 2001

This Article Abstract Full Text (PDF) All Versions of this Article: 276/46/43018    most recent M107823200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zhang, Y. Articles by Mangelsdorf, D. J. Search for Related Content PubMed PubMed Citation Articles by Zhang, Y. Articles by Mangelsdorf, D. J. Social Bookmarking                      What's this?

Regulation of Lipoprotein Lipase by the Oxysterol Receptors, LXR and LXR^*

Yuan Zhang, Joyce J. Repa, Karine Gauthier, and David J. Mangelsdorf^§

From the Department of Pharmacology and Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9050

Received for publication, August 14, 2001, and in revised form, September 7, 2001

	ABSTRACT

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS DISCUSSION REFERENCES

Lipoprotein lipase (LPL) is a key enzyme for lipoprotein metabolism and is responsible for hydrolysis of triglycerides in circulating lipoproteins, releasing free fatty acids to peripheral tissues. In liver, LPL is also believed to promote uptake of high density lipoprotein (HDL)-cholesterol and thereby facilitate reverse cholesterol transport. In this study we show that the Lpl gene is a direct target of the oxysterol liver X receptor, LXR. Mice fed diets containing high cholesterol or an LXR-selective agonist exhibited a significant increase in LPL expression in the liver and macrophages, but not in other tissues (e.g. adipose and muscle). Studies in Lxr-deficient mice confirmed that this response was dependent more on the presence of LXR than LXR. Analysis of the Lpl gene revealed the presence of a functional DR4 LXR response element in the intronic region between exons 1 and 2. This response element directly binds rexinoid receptor (RXR)/LXR heterodimers and is sufficient for rexinoid- and LXR agonist-induced transcription of the Lpl gene. Together, these studies further distinguish the roles of LXR and  and support a growing body of evidence that LXRs function as key regulators of lipid metabolism and are anti-atherogenic.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS DISCUSSION REFERENCES

Chylomicrons and very low density lipoprotein particles are the main carriers of triglycerides in plasma. LPL¹ is synthesized in parenchymal cells and secreted and transported to the endothelial surface, where it is activated to hydrolyze triglycerides present in circulating large lipoproteins (1). Free fatty acids and monoglycerides are released and taken up by tissues to be either re-esterified for storage, used for fuel or lipid synthesis. LPL activity is also essential for the processing of triglyceride-rich lipoproteins into HDL (2). In addition to its enzymatic activity, LPL has been proposed to be a bridging factor that facilitates the uptake of HDL-associated cholesterol esters into the liver (3).

LPL is a member of a family of lipase enzymes that also includes hepatic lipase and pancreatic lipase (4, 5). Although hepatic lipase and pancreatic lipase expression are limited to liver and pancreas, respectively, LPL is expressed at high levels in heart, adipose tissue, skeletal muscle, kidney, and mammary gland, and at lower levels in liver, adrenal, and brain (4, 6-9). LPL activity is regulated by a variety of nutritional factors, as well as insulin, glucocorticoids, catecholamines, pro-inflammatory cytokines, and thiazolidinediones (10, 11). Depending on the stimulus, LPL activity can also vary greatly between tissues. For example, in response to cytokines LPL expression is decreased in adipose tissue and increased in liver (12-14). LPL gene expression is also regulated by a number of transcription factors, including SP1, SREBP-1, and the peroxisome proliferator-activated receptors, PPAR and PPAR (11, 15-20).

LXR and LXR are members of the nuclear hormone receptor superfamily that form heterodimers with RXRs and can be activated by both RXR and LXR ligands (21). RXR/LXR heterodimers activate their target genes by binding to specific response elements (termed LXREs) that contain a hexameric nucleotide direct repeat spaced by four bases (DR4). LXRs are activated by naturally occurring oxysterol ligands (22-24) and regulate the expression of a number of genes involved in cholesterol metabolism (24-33). Studies in Lxr-deficient mice have helped elucidate the role of LXRs as one of the body's main sensors for regulating sterol homeostasis (25, 27, 34, 35). Mice harboring Lxr-null mutations lack the ability to sense dietary cholesterol and as a consequence fail to regulate a number of lipid metabolic pathways, including cholesterol absorption and transport, and bile acid synthesis. Several lines of evidence suggest that, in addition to sterol metabolism, LXRs reciprocally regulate fatty acid metabolism. For example, in wild-type mice dietary cholesterol induces a marked increase in fatty acid synthesis and accumulation of hepatic triglycerides, whereas cholesterol levels are maintained at normal levels due to increased catabolism. This phenotype is reversed in Lxr knockout animals, which accumulate high levels of cholesterol but show no increase in hepatic fatty acid synthesis and have normal triglyceride levels (25). Recently, we have shown that the cholesterol-induced elevation in fatty acid synthesis is due to the direct activation by LXRs of the gene encoding SREBP-1c (36, 37). SREBP-1c is the primary transcription factor responsible for regulating fatty acid synthesis in the liver and peripheral tissues (16, 38). We have suggested that the coordinate regulation of fatty acid and cholesterol metabolism by LXRs provides a means by which the body may protect itself from elevated levels of cholesterol. These findings prompted us to investigate other lipid-regulating genes as potential targets of LXR and LXR action.

In this work we show that cholesterol-induced LPL gene expression in the liver is directly regulated by RXR/LXR heterodimers in a tissue-specific manner and that in vivo this regulation is mediated predominantly by LXR. These studies define a new mechanism for governing tissue-specific LPL expression and further expand the role of the LXRs as key regulators of lipid metabolism.

	EXPERIMENTAL PROCEDURES

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS DISCUSSION REFERENCES

Materials-- LG268, 22(R)-hydroxycholesterol, and T0901317 were acquired from Ligand Pharmaceuticals, Steraloids Inc., and Tularik, Inc, respectively. Lipoprotein-deficient serum was obtained from Intracel Corp. (Rockville, MD).

Plasmids-- Mouse Lpl gene sequences were obtained from GenBank^TM. The promoter region was polymerase chain reaction-amplified from mouse genomic DNA using primers 5'-CCTTAGAAAACGGATCGTAGACTACTCAAC-3' and 5'-CCGCTCGAGCACTCTTCTCGCTTCTAGAGGCGTCTG-3'. A fragment spanning nucleotide 289 to +752 of the promoter was cloned into SmaI-XhoI sites of pGL2-basic vector (Promega). Mutations at the DR4.2 site (+635) were created by SOE (Splicing by Overlap Extention) polymerase chain reaction (39) using primers 5'-CTGTAGTGAGGGGTGGTGAGGTCCCTATAGGGAA-3' and 5'-CTATAGGGACCTCACCACCCCTCACTACAGCTTTG-3' (mutated nucleotides are underlined). To create DR4.1-TK-LUC and DR4.2-TK-LUC, oligonucleotides (sequences shown in Fig. 4) with BamHI overhang sequences were ligated into the BamHI site of the TK-LUC vector. All constructs were verified by sequencing.

Animal Studies-- Animal experiments were approved by the Institution Animal Care and Research Advisory Committee of the University of Texas Southwestern Medical Center and were conducted as described previously (27). Mice were fed ad libitum Teklad 7001 rodent diet supplemented with cholesterol and receptor agonists or vehicle. The rexinoid LG268 was solubilized at 4.5 mg/ml in a vehicle containing 0.9% carboxymethylcellulose, 9% polyethylene glycol 400, and 0.05% Tween 80 and provided in the diet to give a final concentration of 30 mg/kg body weight. The LXR agonist T0901317 was solubilized in a vehicle containing 1% methylcellulose and 1% Tween 80 and administered by oral gavage or provided in the diet at a dose of 50 mg/kg body weight.

Northern Analysis-- RNA was extracted and used in Northern analysis as described previously (25). For these experiments poly(A)⁺ RNA (5 µg/lane) or total RNA (10 µg/lane) was separated on 1% formaldehyde agarose gels, transferred to nylon membranes, and probed with ³²P-labeled human LPL or mouse actin or cyclophilin cDNAs. The human LPL cDNA probe has been described previously (40).

Macrophage Experiments-- Peritoneal macrophages were obtained from thioglycolate-injected male mice of wild-type or Lxr// genotype as described in a previous study (31). Cells were pooled from four wild-type or five Lxr// mice and distributed on two plates, one for each treatment condition. Cells were allowed to adhere for 7 h in DMEM containing10% fetal bovine serum and penicillin/streptomycin. The medium was then replaced with DMEM supplemented with 10% lipoprotein-deficient serum, penicillin/streptomycin, and either vehicle (Me₂SO) or 10 µM LXR agonist (T0901317) and incubated for 42 h.

Cell Culture and Cotransfection Assays-- The human embryonic kidney cell line, HEK 293, was maintained at 37 °C, 5% CO₂ in DMEM containing 10% fetal bovine serum. Transfections were performed in 96-well plates in media containing 10% dextran-charcoal-stripped fetal bovine serum using the calcium phosphate coprecipitation technique (41). Ligands were added at final concentrations of 0.1 µM LG268 and 5 µM 22(R)-hydroxycholesterol. All transfection data were normalized using an internal -galactosidase marker and represent the mean of triplicate assays.

Electrophoretic Mobility Shift Assay-- Electrophoretic mobility shift assay was performed as described previously (42). Sequences of the Lpl DR4.1, DR4.2, and DR4.2m elements are shown in Figs. 4 and 5. Competitor DR4 containing the perfect tandem repeat of AGGTCA was described previously (42). After electrophoresis, the gel was dried at 80 °C for 1.5 h and autoradiographed with intensifying screens at 80 °C overnight.

	RESULTS

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS DISCUSSION REFERENCES

Liver LPL Gene Expression Is Induced by Cholesterol and Synthetic RXR/LXR Agonists-- Previous work has shown that the hepatic accumulation of triglycerides in cholesterol-fed mice is dependent on the expression of LXR (25). To explore the possibility that changes in hepatic LPL expression are associated with this response, wild-type, Lxr/, Lxr/, and Lxr// mice were treated with various dietary regimens for 12 h or 7-10 days and then sacrificed, and hepatic LPL expression was examined by Northern analysis. On a low cholesterol diet in the absence of added agonists, LPL expression in the liver was barely detectable regardless of genotype (Vehicle lanes in Fig. 1). After feeding a diet rich in cholesterol for 7 days, which is known to generate endogenous oxysterol LXR ligands (43), LPL mRNA expression was increased 2.5- to 5-fold in wild-type mice (Fig. 1, A and B). In parallel experiments, treatment with a potent synthetic LXR agonist (27) resulted in a 12- to 17-fold increase in LPL mRNA in wild-type mice (Fig. 1, A and B). Elevation of LPL mRNA was also evident after just one 12-h treatment with LXR agonist (Fig. 1C), suggesting that Lpl is a direct LXR target gene. Treatment of wild-type mice for 10 days (Fig. 1C) or 12 h (Fig. 1D) with the RXR agonist LG268 (27) also resulted in activation of hepatic LPL gene expression, consistent with the notion that RXR works as a permissive heterodimer with LXR (42). Significantly, hepatic LPL expression induced by either LXR or RXR agonists was virtually absent in mice lacking both LXRs (Fig. 1, C and D). The RXR/LXR-induced expression of LPL was still observed in the Lxr knockout mice (Fig. 1B) but was not present in the Lxr knockout mice (Fig. 1A). These data indicate that LPL expression in the liver is regulated by the RXR/LXR heterodimer. In addition, because the liver expresses both LXR and  subtypes, these data suggest that Lpl is predominantly an LXR target gene. It is of interest that in these experiments high cholesterol diets did not induce LPL expression in either the Lxr or  knockout animals (Fig. 1, A and B), even though the potent synthetic agonist did. At present, the significance of this finding is unknown but could reflect differences in the pharmacology of the synthetic agonists versus endogenous ligands, or differences in the strain background of the Lxr knockout (which is in an A129 background) versus Lxr knockout (which is in a C57BL/6 and A129 mixed background) animals. In any case, these experiments show unequivocally that the induction of LPL expression requires the expression of at least one LXR subtype.

View larger version (57K): [in this window] [in a new window]   Fig. 1.   Liver LPL mRNA expression is induced by cholesterol and synthetic RXR/LXR agonists. A, male A129 wild-type and Lxr/ mice were fed chow diets containing vehicle (Veh) or 2% cholesterol (2% Chol). A third group of mice was fed a chow diet and gavaged once a day with 50 mg/kg body weight LXR agonist T0901317 (LXR Ag). On day 7, mRNA was isolated from livers of five different animals per group, and each mRNA preparation was pooled for Northern analysis. Results were quantified by phosphorimaging, standardized against actin, and mathematically adjusted to yield a unit of 1 for the wild-type group receiving the control diet. B, male mixed-strain (A129/C57BL/6) wild-type and Lxr/ mice were treated the same as described in A. C, male mixed-strain (A129/C57BL/6) wild-type and Lxr// mice were fed 0.2% cholesterol diets containing vehicle (Veh), 30 mg/kg body weight LG268 (RXR Ag), or 50 mg/kg body weight T0901317 (LXR Ag) for 10 days. Liver mRNA was isolated and pooled as above (n = 6) for Northern analysis. D, male mixed-strain (A129/C57BL/6) wild-type and Lxr// mice were treated as in C for 12 h. Liver mRNA was isolated, and Northern analysis was performed as above on individual mice. Results shown are representative of three independent experiments. The mouse LPL mRNA migrates as a doublet of 3.4 and 3.6 kb (4, 50).

LXR-dependent Regulation of LPL Expression in Other Tissues-- We next looked at regulation of LPL expression in other known LXR target tissues. Macrophages and adipose tissue express high levels of LXR proteins and are known to regulate several LXR target genes (27, 31, 36). LPL expression in peritoneal macrophages was stimulated 2-fold after a 42-h treatment with LXR agonist (Fig. 2A). Although the induction was not as high as that seen in liver (Fig. 1), the effect in macrophages was consistently reproducible (in four independent experiments). It is also of significance to note that the basal expression in macrophages was higher, which affected the fold induction but not the maximal level of expression induced by the LXR agonist. This induction was absent in macrophages isolated from Lxr/ double-knockout mice. In contrast, in adipose tissue, which expresses higher basal levels of LPL, the LXR agonist exhibited no significant effect on LPL expression in either mouse genotype after a 12-h or 10-day oral administration of the drug (Fig. 2, B and C, respectively). We also looked at expression of LPL in heart, muscle, kidney, intestine, and adrenals, tissues that are known to express LPL. Similar to the results found in adipose tissue, none of these other tissues exhibited LXR-dependent regulation of LPL (Fig. 2D). These data support the conclusion that LPL expression is differentially regulated by LXR in a tissue-specific manner.

View larger version (59K): [in this window] [in a new window]   Fig. 2.   LPL mRNA expression in other tissues. A, peritoneal macrophages were isolated from male A129/C57BL/6 mice as described (31) and incubated with 10% lipoprotein-deficient serum in the presence of vehicle (Veh) or 10 µM T0901317 (LXR Ag) for 42 h. Total RNA was isolated, and Northern analysis was performed as in Fig. 1. Results shown are representative of four independent experiments. B and C, white adipose tissue mRNA from male mixed strain mice treated for 12 h (B) or 10 days (C) was prepared as described in Fig. 1D and used for Northern analysis (n = 3 for 12-h and n = 5 for 10-day experiments). D, male A129 wild-type mice were fed chow diets containing vehicle (Veh) or 50 mg/kg body weight T0901317 (LXR Ag) for 7 days. Tissues were obtained and total RNA was isolated from 10 mice of each group. mRNA was pooled for Northern analysis as described in Fig. 1 (n = 5 for each lane). Fold induction was calculated after standardizing to cyclophilin, using the average of both groups for each treatment.

Identification of a Functional RXR/LXR Binding Site in the First Intron of the Mouse LPL Gene-- The mouse Lpl gene promoter and partial coding sequences were obtained from GenBank^TM. A computer-assisted search for potential LXR response elements was performed. The search revealed two DR4-like sequences (Fig. 3A), one at 274 to 259 (DR4.1, 5'-TAAATCagtgTAAACC-3') and another at +635 to +650 (DR4.2, 5'-TGACCGgtggTGACCT-3'). Electrophoresis mobility gel shift assays were performed to investigate the direct binding of receptors to each sequence. An oligonucleotide containing the DR4.2 sequence was radiolabeled and used in the experiments shown in Fig. 3 (B and C). The DR4.2 oligo produced a significant band shift when incubated with in vitro translated RXR/LXR protein (Fig. 3B, lane 4) but not when incubated with either receptor alone (lanes 2 and 3). Binding of the RXR/LXR heterodimer was completely inhibited by a 10- and 50-fold molar excess of either unlabeled DR4.2 (Fig. 3B, lanes 5 and 6) or the canonical DR4 LXRE (lanes 11 and 12) oligonucleotide identified previously (42). This inhibition was specific, because a mutated version of the DR4.2 element (see Fig. 5A for sequence) was unable to compete for binding, even at a 50-fold molar excess (Fig. 3B, lanes 7 and 8). In contrast to the DR4.2 element, the DR4.1 element was unable to compete for binding to the RXR/LXR heterodimer (Fig. 3B, lanes 9 and 10), suggesting that this site does not function as an LXRE.

View larger version (69K): [in this window] [in a new window]   Fig. 3.   The LXR/RXR heterodimer binds to a DR4 in the first intron of the Lpl gene. A, the location and sequences of DR4 elements in mouse Lpl gene. Exon 1 indicates the first exon of the Lpl gene. The asterisk marks the translation start site of LPL. B and C, electrophoretic mobility shift assays were performed as outlined under "Experimental Procedures." 32P-Labeled DR4.2 oligonucleotide was incubated with in vitro synthesized FLAG-tagged human LXR, LXR, and/or RXR proteins as indicated. Competitions were performed using unlabeled oligonucleotides at 10- and 50-fold molar excess as indicated.

We also looked at the ability of LXR to bind to the two sites. LXR protein was radiolabeled by in vitro translation to a specific activity that was similar to LXR and tested in the band-shift assay. In contrast to LXR (Figs. 3B and 3C, lane 6), the RXR/LXR heterodimer bound only weakly (~10-fold less) to the DR4.2 oligonucleotide (Fig. 3C, lane 4). As expected, LXR exhibited no binding to the DR4.1 site (data not shown). Similar results were seen using either human or mouse receptor proteins.

To test the ability of the DR4-like elements to function as LXR response elements, one copy of either the DR4.1 or DR4.2 elements was cloned into the luciferase reporter gene TK-Luc and cotransfected into HEK 293 cells with or without expression plasmids for mouse LXR, LXR, and RXR receptors. After treatment with ethanol vehicle, rexinoid LG268, LXR ligand 22(R)-hydroxycholesterol, or both ligands, the cells were harvested and assayed for luciferase activity (Fig. 4, A and B). Consistent with the band-shift results in Fig. 3, only the DR4.2 element was able to mediate RXR/LXR-dependent transactivation of the reporter gene. In addition, LXR-mediated transcription was significantly higher than that of LXR, further supporting the notion that the Lpl gene is more selectively activated by LXR than LXR.

View larger version (18K): [in this window] [in a new window]   Fig. 4.   The DR4 sequence in the first intron of the Lpl gene mediates transactivation by the LXR/RXR heterodimer. One copy of the DR4.1 (A) or DR4.2 (B) oligonucleotides was cloned into the TK-Luc reporter vector and cotransfected into HEK 293 cells with either empty CMX vector (no receptor) or both CMX-mLXR (or CMX-mLXR) and CMX-mRXR. Cells were then treated with vehicle control (ETOH), 0.1 µM LG268, 5 µM 22(R)-hydroxycholesterol (22(R)-HC), or both ligands. Luciferase activity was measured as described under "Experimental Procedures." The results are expressed as relative light units (RLU) and represent the mean ± S.D. of three independent experiments.

The DR4.2 Sequence Is a Functional LXRE in the Full-length LPL Promoter-- To demonstrate that the DR4.2 element identified above functions as an LXRE in the context of the Lpl gene promoter, the mouse Lpl gene from 289 to +752 was cloned into the luciferase vector pGL2 and the resultant reporter gene (pLPL_wt-Luc) was tested for LXR-dependent transactivation. This portion of the Lpl gene contains both the DR4.1 and DR4.2 sequences (Fig. 5A). A similar construct in which the DR4.2 site was mutated to destroy LXR binding (see Fig. 3B, lanes 7 and 8) was also tested. As shown in Fig. 5B, the wild-type promoter conferred significant RXR/LXR-dependent transactivation to the Lpl promoter, whereas the mutated version in which the DR4.2 site was altered (pLPL_mut-Luc) did not. We conclude from these data that the Lpl promoter contains a functional LXRE located within the first intron of the gene. In a similar experiment LXR was also able to mediate activation of the wild-type promoter, albeit at a significantly reduced level (data not shown). Taken together, these results support the conclusion that the Lpl gene is a direct target of LXR-mediated regulation by oxysterols. Furthermore, these data suggest that this regulation is governed primarily by LXR.

View larger version (21K): [in this window] [in a new window]   Fig. 5.   The DR4.2 sequence is a functional LXRE in the context of the native LPL gene. A, scheme depicting the luciferase reporter gene containing the native Lpl promoter and first intron sequences. Wild-type and mutated (underlined) DR4.2 sequences are shown. B, wild-type and mutated reporter genes were cotransfected into HEK 293 cells with either empty CMX vector (no receptor) or both CMX-mLXR and CMX-mRXR. Transfected cells were treated with vehicle control (ETOH), or LG268 (0.1 µM) and 22(R)-hydroxycholesterol (22(R)-HC) (5 µM). Luciferase activity is depicted as described in Fig. 4.

	DISCUSSION

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS DISCUSSION REFERENCES

In this study we show that the mouse Lpl gene is a direct target of the oxysterol receptor, LXR. The activation of Lpl gene transcription by LXR is mediated via an LXRE in the first intron of the mouse gene. This LXRE is conserved in the human Lpl gene as well, indicating that LXR responsiveness is also conserved in humans. Furthermore, we show that LXR regulation of LPL expression is tissue-specific. LPL is markedly up-regulated by RXR/LXR agonists in liver and to a lesser extent in macrophages but not in adipose, muscle, kidney, adrenal, intestine, or heart.

One of the questions raised by these findings is what is the physiological basis of the tissue-specific regulation of LPL by LXRs. LPL is the rate-limiting enzyme that catalyzes the hydrolysis of lipoprotein triglycerides for uptake of fatty acids into adjacent tissues. Thus, in tissues such as adipose and muscle, LPL activity is required to meet the high demand these tissues have for free fatty acids. Despite the fact that LXRs are expressed abundantly in adipose and are known to regulate other adipose target genes, such as SREBP-1c, it is of significance that Lpl is not regulated by LXRs in this tissue. One explanation for this lack of regulation may be that subtle changes in the expression of LPL are masked by the already high basal level of LPL expression in adipose. However, it is worth noting that other transcription factors, in particular PPAR (see below), are able to regulate Lpl in this tissue. A more likely explanation is that tissue-specific regulation of Lpl by LXRs in liver and macrophages is directly linked to the role LXRs play in maintaining whole body cholesterol balance.

One attractive hypothesis is that LXR up-regulates LPL to help the body clear the serum of cholesterol-rich lipoproteins (via macrophages) and transport this cholesterol (via HDL) back to the liver for catabolism and elimination. At present the function of LPL in macrophages and liver is controversial and just beginning to be elucidated. LPL has been suggested to have both pro- and anti-atherogenic properties in these tissues (44). For example, in macrophages LPL has been shown to facilitate uptake of cholesterol esters, presumably by remodeling triglyceride-rich chylomicrons and very low density lipoprotein into chylomicron remnants and low density lipoprotein that are then taken up by macrophages (45). Under pathogenic conditions, the excess cholesterol build-up in macrophages would lead to the development of foam cells. However, under non-pathogenic conditions, this cholesterol ester may be converted to oxysterols and free cholesterol that are effluxed out of the macrophage into HDL and transported to the liver. In the liver, LPL expression is normally undetectable in adult animals (9, 46), but as shown by this study hepatic LPL expression is up-regulated markedly by high cholesterol diets and LXR agonists (Fig. 1). Several recent studies implicate the role of hepatic LPL expression as being anti-atherogenic by helping to facilitate reverse cholesterol transport through the HDL pathway. Strauss et al. (2) showed that adenoviral-mediated expression of LPL in Lpl-deficient mice is necessary and sufficient to promote maturation of HDL. It has also been shown that LPL can mediate the selective uptake of HDL-cholesterol into liver cells by a mechanism that evidently does not involve the enzymatic activity of the lipase (3). Our observation that LPL is induced by LXR and its agonists and that cholesterol induction of LPL is LXR-dependent is consistent with the recent identification of other LXR target genes in macrophages and liver that are in the reverse cholesterol transport pathway. These genes include the ABC sterol transport proteins ABCA1, ABCG1, ABCG5, and ABCG8; apolipoprotein E; cholesterol ester transfer protein; and cholesterol 7-hydroxylase (24-33).² Together these findings support a growing body of evidence that demonstrates LXRs are key sensors of sterol metabolism and maintain normal cholesterol balance by promoting sterol efflux from peripheral cells, increasing circulating HDL-cholesterol, increasing hepatic sterol catabolism and excretion, and inhibiting further sterol absorption (25, 27, 34, 35).

Another conclusion that can be extrapolated from this and other recent studies is that LPL expression is coordinately regulated by multiple dietary factors via nuclear receptors. Here we have shown that sterol-mediated regulation of Lpl requires the LXRs. Previous work has shown that, in macrophages, high glucose induces LPL expression, in part through enhanced expression of PPAR (20). Fatty acids and other PPAR agonists also induce LPL expression in the liver through a pathway that may involve LXR activation (11, 47). TNF has also been shown to enhance both fatty acid synthesis and LPL activity in liver (12, 14). The mechanism of TNF stimulation in these cases is also believed to be indirect, suggesting that either PPAR or LXR may be modulating TNF induction of LPL. Finally, in adipocytes, LPL expression is specifically induced by PPAR agonists (11), but not by LXR agonists (Fig. 2), even though LXR is abundantly expressed in adipose tissue and can potently up-regulate other adipose target genes such as SREBP-1c (36). These data support the notion that the LXRs (oxysterol receptors) and PPARs (fatty acid receptors) define two distinct, but overlapping metabolic pathways that govern fatty acid metabolism in response to different dietary lipids (i.e. cholesterol and fatty acids).

A final intriguing observation from this work is the finding that LXR is a more selective regulator of Lpl than LXR. In liver, LPL synthesis has been reported to be confined to Kupffer cells (48), although there is evidence that in newborn rats LPL is expressed in hepatocytes (49). Although it is possible that part of the LXR selectivity for LPL expression is attributable to differential cell type expression of the two LXR genes, we note that the in vitro data on Lpl promoter binding and activation by the LXRs (Figs. 3 and 4) support the idea that LXR has a higher affinity than LXR for the Lpl LXRE. In either case, the identification of Lpl as an LXR-selective target gene is in keeping with the previous notion that LXR and LXR have distinct targets in vivo (25, 34). Because LXR agonists have pharmacologic effects that are both desirable (e.g. increased reverse cholesterol transport) (27, 35) and undesirable (e.g. hypertriglyceridemia) (37), the identification of specific LXR or LXR agonists or antagonists may have considerable therapeutic potential.

	ACKNOWLEDGEMENTS

We thank Dr. Richard Heyman at X-Ceptor Therapeutics and Dr. Bei Shan at Tularik for RXR and LXR agonists, respectively; Dr. Peter Tontonoz for reagents for macrophage experiments; and Dr. Johan Auwerx for human LPL cDNA. We thank members of the Mango laboratory for critically reading the manuscript.

	FOOTNOTES

^* This work was funded by the Howard Hughes Medical Institute (HHMI) and grants from the Robert A. Welch Foundation, the Human Frontier Science Program, and the National Institutes of Health (Specialized Programs of Research Excellence in Lung Cancer).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.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EMBL Data Bank with accession number(s) M63335 (51).

Research Associates of the HHMI.

^§ An Investigator of the HHMI. To whom correspondence should be addressed: HHMI, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9050. Tel.: 214-648-6349; Fax: 214-648-5419; E-mail: davo.mango@utsouthwestern.edu.

Published, JBC Papers in Press, September 18, 2001, DOI 10.1074/jbc.M107823200

² J. J. Repa and D. J. Mangelsdorf, manuscript in preparation.

	ABBREVIATIONS

The abbreviations used are: LPL, lipoprotein lipase; HDL, high density lipoprotein; SREBP-1, sterol regulatory element binding protein-1; PPAR, peroxisome proliferator-activated receptor; LXR, liver X receptor; RXR, rexinoid receptor; LXRE, LXR response element; DR4, direct repeat spaced by four bases; ABC, ATP-binding cassette; TNF, tumor necrosis factor; DMEM, Dulbecco's modified Eagle's medium.

	REFERENCES

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS DISCUSSION REFERENCES

CiteULike

Complore

Connotea

Del.icio.us

Digg

Reddit

Technorati

This article has been cited by other articles:

				L. Cruz-Garcia, A. Saera-Vila, I. Navarro, J. Calduch-Giner, and J. Perez-Sanchez Targets for TNF{alpha}-induced lipolysis in gilthead sea bream (Sparus aurata L.) adipocytes isolated from lean and fat juvenile fish J. Exp. Biol., July 15, 2009; 212(14): 2254 - 2260. [Abstract] [Full Text] [PDF]

				T. Nakajima, N. Tanaka, H. Kanbe, A. Hara, Y. Kamijo, X. Zhang, F. J. Gonzalez, and T. Aoyama Bezafibrate at Clinically Relevant Doses Decreases Serum/Liver Triglycerides via Down-Regulation of Sterol Regulatory Element-Binding Protein-1c in Mice: A Novel Peroxisome Proliferator-Activated Receptor {alpha}-Independent Mechanism Mol. Pharmacol., April 1, 2009; 75(4): 782 - 792. [Abstract] [Full Text] [PDF]

				A. Kratzer, M. Buchebner, T. Pfeifer, T. M. Becker, G. Uray, M. Miyazaki, S. Miyazaki-Anzai, B. Ebner, P. G. Chandak, R. S. Kadam, et al. Synthetic LXR agonist attenuates plaque formation in apoE-/- mice without inducing liver steatosis and hypertriglyceridemia J. Lipid Res., February 1, 2009; 50(2): 312 - 326. [Abstract] [Full Text] [PDF]

				J. F. Rippmann, C. Schoelch, T. Nolte, H. Pavliska, A. van Marle, H. van Es, and J. Prestle Improved lipid profile through liver-specific knockdown of liver X receptor {alpha} in KKAy diabetic mice J. Lipid Res., January 1, 2009; 50(1): 22 - 31. [Abstract] [Full Text] [PDF]

				S. Bultel, L. Helin, V. Clavey, G. Chinetti-Gbaguidi, E. Rigamonti, M. Colin, J.-C. Fruchart, B. Staels, and S. Lestavel Liver X Receptor Activation Induces the Uptake of Cholesteryl Esters From High Density Lipoproteins in Primary Human Macrophages Arterioscler. Thromb. Vasc. Biol., December 1, 2008; 28(12): 2288 - 2295. [Abstract] [Full Text] [PDF]

				D. Peng, R. A. Hiipakka, Q. Dai, J. Guo, C. A. Reardon, G. S. Getz, and S. Liao Antiatherosclerotic Effects of a Novel Synthetic Tissue-Selective Steroidal Liver X Receptor Agonist in Low-Density Lipoprotein Receptor-Deficient Mice J. Pharmacol. Exp. Ther., November 1, 2008; 327(2): 332 - 342. [Abstract] [Full Text] [PDF]

				V. K. Khor, M. H. Tong, Y. Qian, and W.-C. Song Gender-Specific Expression and Mechanism of Regulation of Estrogen Sulfotransferase in Adipose Tissues of the Mouse Endocrinology, November 1, 2008; 149(11): 5440 - 5448. [Abstract] [Full Text] [PDF]

				S. Colin, E. Bourguignon, A.-B. Boullay, J.-J. Tousaint, S. Huet, F. Caira, B. Staels, S. Lestavel, J.-M. A. Lobaccaro, and P. Delerive Intestine-Specific Regulation of PPAR{alpha} Gene Transcription by Liver X Receptors Endocrinology, October 1, 2008; 149(10): 5128 - 5135. [Abstract] [Full Text] [PDF]

				T. Wada, H. S. Kang, A. M. Jetten, and W. Xie The Emerging Role of Nuclear Receptor ROR{alpha} and Its Crosstalk with LXR in Xeno- and Endobiotic Gene Regulation Experimental Biology and Medicine, October 1, 2008; 233(10): 1191 - 1201. [Abstract] [Full Text] [PDF]

				C. A. Major, K. Ryan, A. J. Bennett, A. L. Lock, D. E. Bauman, and A. M. Salter Inhibition of stearoyl CoA desaturase activity induces hypercholesterolemia in the cholesterol-fed hamster J. Lipid Res., July 1, 2008; 49(7): 1456 - 1465. [Abstract] [Full Text] [PDF]

				T. Wada, H. S. Kang, M. Angers, H. Gong, S. Bhatia, S. Khadem, S. Ren, E. Ellis, S. C. Strom, A. M. Jetten, et al. Identification of Oxysterol 7{alpha}-Hydroxylase (Cyp7b1) as a Novel Retinoid-Related Orphan Receptor {alpha} (ROR{alpha}) (NR1F1) Target Gene and a Functional Cross-Talk between ROR{alpha} and Liver X Receptor (NR1H3) Mol. Pharmacol., March 1, 2008; 73(3): 891 - 899. [Abstract] [Full Text] [PDF]

				Q. Li, M.-J. Chu, and J. Xu Tissue- and Nuclear Receptor-Specific Function of the C-Terminal LXXLL Motif of Coactivator NCoA6/AIB3 in Mice Mol. Cell. Biol., December 1, 2007; 27(23): 8073 - 8086. [Abstract] [Full Text] [PDF]

				J. Westerbacka, M. Kolak, T. Kiviluoto, P. Arkkila, J. Siren, A. Hamsten, R. M. Fisher, and H. Yki-Jarvinen Genes Involved in Fatty Acid Partitioning and Binding, Lipolysis, Monocyte/Macrophage Recruitment, and Inflammation Are Overexpressed in the Human Fatty Liver of Insulin-Resistant Subjects Diabetes, November 1, 2007; 56(11): 2759 - 2765. [Abstract] [Full Text] [PDF]

				M. Gustafsson, M. Levin, K. Skalen, J. Perman, V. Friden, P. Jirholt, S.-O. Olofsson, S. Fazio, M. F. Linton, C. F. Semenkovich, et al. Retention of Low-Density Lipoprotein in Atherosclerotic Lesions of the Mouse: Evidence for a Role of Lipoprotein Lipase Circ. Res., October 12, 2007; 101(8): 777 - 783. [Abstract] [Full Text] [PDF]

				G. Qiu and J. S. Hill Atorvastatin decreases lipoprotein lipase and endothelial lipase expression in human THP-1 macrophages J. Lipid Res., October 1, 2007; 48(10): 2112 - 2122. [Abstract] [Full Text] [PDF]

				C. J. Delvecchio, P. Bilan, K. Radford, J. Stephen, B. L. Trigatti, G. Cox, K. Parameswaran, and J. P. Capone Liver X Receptor Stimulates Cholesterol Efflux and Inhibits Expression of Proinflammatory Mediators in Human Airway Smooth Muscle Cells Mol. Endocrinol., June 1, 2007; 21(6): 1324 - 1334. [Abstract] [Full Text] [PDF]

				M. M. Beyea, C. L. Heslop, C. G. Sawyez, J. Y. Edwards, J. G. Markle, R. A. Hegele, and M. W. Huff Selective Up-regulation of LXR-regulated Genes ABCA1, ABCG1, and APOE in Macrophages through Increased Endogenous Synthesis of 24(S),25-Epoxycholesterol J. Biol. Chem., February 23, 2007; 282(8): 5207 - 5216. [Abstract] [Full Text] [PDF]

				J.-Y. Cha and J. J. Repa The Liver X Receptor (LXR) and Hepatic Lipogenesis: THE CARBOHYDRATE-RESPONSE ELEMENT-BINDING PROTEIN IS A TARGET GENE OF LXR J. Biol. Chem., January 5, 2007; 282(1): 743 - 751. [Abstract] [Full Text] [PDF]

				D. D. Moore, S. Kato, W. Xie, D. J. Mangelsdorf, D. R. Schmidt, R. Xiao, and S. A. Kliewer International Union of Pharmacology. LXII. The NR1H and NR1I Receptors: Constitutive Androstane Receptor, Pregnene X Receptor, Farnesoid X Receptor {alpha}, Farnesoid X Receptor beta, Liver X Receptor {alpha}, Liver X Receptor beta, and Vitamin D Receptor Pharmacol. Rev., December 1, 2006; 58(4): 742 - 759. [Abstract] [Full Text] [PDF]

				L. K. Curtiss, D. T. Valenta, N. J. Hime, and K.-A. Rye What Is So Special About Apolipoprotein AI in Reverse Cholesterol Transport? Arterioscler. Thromb. Vasc. Biol., January 1, 2006; 26(1): 12 - 19. [Abstract] [Full Text] [PDF]

				M. Chen, S. Beaven, and P. Tontonoz Identification and characterization of two alternatively spliced transcript variants of human liver X receptor alpha J. Lipid Res., December 1, 2005; 46(12): 2570 - 2579. [Abstract] [Full Text] [PDF]

				T. Hu, P. Foxworthy, A. Siesky, J. V. Ficorilli, H. Gao, S. Li, M. Christe, T. Ryan, G. Cao, P. Eacho, et al. Hepatic Peroxisomal Fatty Acid {beta}-Oxidation Is Regulated by Liver X Receptor {alpha} Endocrinology, December 1, 2005; 146(12): 5380 - 5387. [Abstract] [Full Text] [PDF]

				S. L. Sabol, H. B. Brewer Jr., and S. Santamarina-Fojo The human ABCG1 gene: identification of LXR response elements that modulate expression in macrophages and liver J. Lipid Res., October 1, 2005; 46(10): 2151 - 2167. [Abstract] [Full Text] [PDF]

				F. Y. Lee, H. R. Kast-Woelbern, J. Chang, G. Luo, S. A. Jones, M. C. Fishbein, and P. A. Edwards {alpha}-Crystallin Is a Target Gene of the Farnesoid X-activated Receptor in Human Livers J. Biol. Chem., September 9, 2005; 280(36): 31792 - 31800. [Abstract] [Full Text] [PDF]

				A. I. Shulman and D. J. Mangelsdorf Retinoid X Receptor Heterodimers in the Metabolic Syndrome N. Engl. J. Med., August 11, 2005; 353(6): 604 - 615. [Full Text] [PDF]

				A. Bobard, I. Hainault, P. Ferre, F. Foufelle, and P. Bossard Differential Regulation of Sterol Regulatory Element-binding Protein 1c Transcriptional Activity by Insulin and Liver X Receptor during Liver Development J. Biol. Chem., January 7, 2005; 280(1): 199 - 206. [Abstract] [Full Text] [PDF]

				F. Blaschke, O. Leppanen, Y. Takata, E. Caglayan, J. Liu, M. C. Fishbein, K. Kappert, K. I. Nakayama, A. R. Collins, E. Fleck, et al. Liver X Receptor Agonists Suppress Vascular Smooth Muscle Cell Proliferation and Inhibit Neointima Formation in Balloon-Injured Rat Carotid Arteries Circ. Res., December 10, 2004; 95(12): e110 - e123. [Abstract] [Full Text] [PDF]

				K. R Steffensen, S. Y. Neo, T. M Stulnig, V. B Vega, S. S Rahman, G. U Schuster, J.-A. Gustafsson, and E. T Liu Genome-wide expression profiling; a panel of mouse tissues discloses novel biological functions of liver X receptors in adrenals J. Mol. Endocrinol., December 1, 2004; 33(3): 609 - 622. [Abstract] [Full Text] [PDF]

				A. C. Li and C. K. Glass PPAR- and LXR-dependent pathways controlling lipid metabolism and the development of atherosclerosis J. Lipid Res., December 1, 2004; 45(12): 2161 - 2173. [Abstract] [Full Text] [PDF]

				Y. Inoue, J. Inoue, G. Lambert, S. H. Yim, and F. J. Gonzalez Disruption of Hepatic C/EBP{alpha} Results in Impaired Glucose Tolerance and Age-dependent Hepatosteatosis J. Biol. Chem., October 22, 2004; 279(43): 44740 - 44748. [Abstract] [Full Text] [PDF]

				D. S. Ory Nuclear Receptor Signaling in the Control of Cholesterol Homeostasis: Have the Orphans Found a Home? Circ. Res., October 1, 2004; 95(7): 660 - 670. [Abstract] [Full Text] [PDF]

				Y. Liang, X.-C. Jiang, R. Liu, G. Liang, T. P. Beyer, H. Gao, T. P. Ryan, S. Dan Li, P. I. Eacho, and G. Cao Liver X Receptors (LXRs) Regulate Apolipoprotein AIV-Implications of the Antiatherosclerotic Effect of LXR Agonists Mol. Endocrinol., August 1, 2004; 18(8): 2000 - 2010. [Abstract] [Full Text] [PDF]

				T. P. Beyer, R. J. Schmidt, P. Foxworthy, Y. Zhang, J. Dai, W. R. Bensch, R. F. Kauffman, H. Gao, T. P. Ryan, X.-C. Jiang, et al. Coadministration of a Liver X Receptor Agonist and a Peroxisome Proliferator Activator Receptor-{alpha} Agonist in Mice: Effects of Nuclear Receptor Interplay on High-Density Lipoprotein and Triglyceride Metabolism in Vivo J. Pharmacol. Exp. Ther., June 1, 2004; 309(3): 861 - 868. [Abstract] [Full Text] [PDF]

				G. Xu, L.-x. Pan, H. Li, Q. Shang, A. Honda, S. Shefer, J. Bollineni, Y. Matsuzaki, G. S. Tint, and G. Salen Dietary cholesterol stimulates CYP7A1 in rats because farnesoid X receptor is not activated Am J Physiol Gastrointest Liver Physiol, May 1, 2004; 286(5): G730 - G735. [Abstract] [Full Text] [PDF]

				J. B. Seo, H. M. Moon, W. S. Kim, Y. S. Lee, H. W. Jeong, E. J. Yoo, J. Ham, H. Kang, M.-G. Park, K. R. Steffensen, et al. Activated Liver X Receptors Stimulate Adipocyte Differentiation through Induction of Peroxisome Proliferator-Activated Receptor {gamma} Expression Mol. Cell. Biol., April 15, 2004; 24(8): 3430 - 3444. [Abstract] [Full Text] [PDF]

				Y. Zhang, J. J. Repa, Y. Inoue, G. P. Hayhurst, F. J. Gonzalez, and D. J. Mangelsdorf Identification of a Liver-Specific Uridine Phosphorylase that Is Regulated by Multiple Lipid-Sensing Nuclear Receptors Mol. Endocrinol., April 1, 2004; 18(4): 851 - 862. [Abstract] [Full Text] [PDF]

				D. H. Volle, J. J. Repa, A. Mazur, C. L. Cummins, P. Val, J. Henry-Berger, F. Caira, G. Veyssiere, D. J. Mangelsdorf, and J.-M. A. Lobaccaro Regulation of the Aldo-Keto Reductase Gene akr1b7 by the Nuclear Oxysterol Receptor LXR{alpha} (Liver X Receptor-{alpha}) in the Mouse Intestine: Putative Role of LXRs in Lipid Detoxification Processes Mol. Endocrinol., April 1, 2004; 18(4): 888 - 898. [Abstract] [Full Text] [PDF]

				A. M. Gotto Jr and E. A. Brinton Assessing low levels of high-density lipoprotein cholesterol as a risk factor in coronary heart disease: A working group report and update J. Am. Coll. Cardiol., March 3, 2004; 43(5): 717 - 724. [Abstract] [Full Text] [PDF]

				D. S. Ng, C. Xie, G. F. Maguire, X. Zhu, F. Ugwu, E. Lam, and P. W. Connelly Hypertriglyceridemia in Lecithin-cholesterol Acyltransferase-deficient Mice Is Associated with Hepatic Overproduction of Triglycerides, Increased Lipogenesis, and Improved Glucose Tolerance J. Biol. Chem., February 27, 2004; 279(9): 7636 - 7642. [Abstract] [Full Text] [PDF]

				M. Ricote, A. F. Valledor, and C. K. Glass Decoding Transcriptional Programs Regulated by PPARs and LXRs in the Macrophage: Effects on Lipid Homeostasis, Inflammation, and Atherosclerosis Arterioscler. Thromb. Vasc. Biol., February 1, 2004; 24(2): 230 - 239. [Abstract] [Full Text]

				K. R. Steffensen and J.-A. Gustafsson Putative Metabolic Effects of the Liver X Receptor (LXR) Diabetes, February 1, 2004; 53(90001): S36 - 42. [Abstract] [Full Text]

				A. Pawar, D. Botolin, D. J. Mangelsdorf, and D. B. Jump The Role of Liver X Receptor-{alpha} in the Fatty Acid Regulation of Hepatic Gene Expression J. Biol. Chem., October 17, 2003; 278(42): 40736 - 40743. [Abstract] [Full Text] [PDF]

				K. S. Bramlett, K. A. Houck, K. M. Borchert, M. S. Dowless, P. Kulanthaivel, Y. Zhang, T. P. Beyer, R. Schmidt, J. S. Thomas, L. F. Michael, et al. A Natural Product Ligand of the Oxysterol Receptor, Liver X Receptor J. Pharmacol. Exp. Ther., October 1, 2003; 307(1): 291 - 296. [Abstract] [Full Text] [PDF]

				P. C. Pircher, J. L. Kitto, M. L. Petrowski, R. K. Tangirala, E. D. Bischoff, I. G. Schulman, and S. K. Westin Farnesoid X Receptor Regulates Bile Acid-Amino Acid Conjugation J. Biol. Chem., July 18, 2003; 278(30): 27703 - 27711. [Abstract] [Full Text] [PDF]

				T. Ide, H. Shimano, T. Yoshikawa, N. Yahagi, M. Amemiya-Kudo, T. Matsuzaka, M. Nakakuki, S. Yatoh, Y. Iizuka, S. Tomita, et al. Cross-Talk between Peroxisome Proliferator-Activated Receptor (PPAR) {alpha} and Liver X Receptor (LXR) in Nutritional Regulation of Fatty Acid Metabolism. II. LXRs Suppress Lipid Degradation Gene Promoters through Inhibition of PPAR Signaling Mol. Endocrinol., July 1, 2003; 17(7): 1255 - 1267. [Abstract] [Full Text] [PDF]

				E. G. Lund, J. G. Menke, and C. P. Sparrow Liver X Receptor Agonists as Potential Therapeutic Agents for Dyslipidemia and Atherosclerosis Arterioscler. Thromb. Vasc. Biol., July 1, 2003; 23(7): 1169 - 1177. [Abstract] [Full Text] [PDF]

				T. Inaba, M. Matsuda, M. Shimamura, N. Takei, N. Terasaka, Y. Ando, H. Yasumo, R. Koishi, M. Makishima, and I. Shimomura Angiopoietin-like Protein 3 Mediates Hypertriglyceridemia Induced by the Liver X Receptor J. Biol. Chem., June 6, 2003; 278(24): 21344 - 21351. [Abstract] [Full Text] [PDF]

				P. Tontonoz and D. J. Mangelsdorf Liver X Receptor Signaling Pathways in Cardiovascular Disease Mol. Endocrinol., June 1, 2003; 17(6): 985 - 993. [Abstract] [Full Text] [PDF]

				X. Hu, S. Li, J. Wu, C. Xia, and D. S. Lala Liver X Receptors Interact with Corepressors to Regulate Gene Expression Mol. Endocrinol., June 1, 2003; 17(6): 1019 - 1026. [Abstract] [Full Text] [PDF]

				S.-W. Kim, K. Park, E. Kwak, E. Choi, S. Lee, J. Ham, H. Kang, J. M. Kim, S. Y. Hwang, Y.-Y. Kong, et al. Activating Signal Cointegrator 2 Required for Liver Lipid Metabolism Mediated by Liver X Receptors in Mice Mol. Cell. Biol., May 15, 2003; 23(10): 3583 - 3592. [Abstract] [Full Text] [PDF]

				B. A. Laffitte, L. C. Chao, J. Li, R. Walczak, S. Hummasti, S. B. Joseph, A. Castrillo, D. C. Wilpitz, D. J. Mangelsdorf, J. L. Collins, et al. Activation of liver X receptor improves glucose tolerance through coordinate regulation of glucose metabolism in liver and adipose tissue PNAS, April 29, 2003; 100(9): 5419 - 5424. [Abstract] [Full Text] [PDF]

				G. Lambert, M. J. A. Amar, G. Guo, H. B. Brewer Jr., F. J. Gonzalez, and C. J. Sinal The Farnesoid X-receptor Is an Essential Regulator of Cholesterol Homeostasis J. Biol. Chem., January 17, 2003; 278(4): 2563 - 2570. [Abstract] [Full Text] [PDF]

				G. Cao, Y. Liang, C. L. Broderick, B. A. Oldham, T. P. Beyer, R. J. Schmidt, Y. Zhang, K. R. Stayrook, C. Suen, K. A. Otto, et al. Antidiabetic Action of a Liver X Receptor Agonist Mediated By Inhibition of Hepatic Gluconeogenesis J. Biol. Chem., January 3, 2003; 278(2): 1131 - 1136. [Abstract] [Full Text] [PDF]

				R. Kaplan, T. Zhang, M. Hernandez, F. X. Gan, S. D. Wright, M. G. Waters, and T.-Q. Cai Regulation of the angiopoietin-like protein 3 gene by LXR J. Lipid Res., January 1, 2003; 44(1): 136 - 143. [Abstract] [Full Text] [PDF]

				M. Merkel, R. H. Eckel, and I. J. Goldberg Lipoprotein lipase: genetics, lipid uptake, and regulation J. Lipid Res., December 1, 2002; 43(12): 1997 - 2006. [Abstract] [Full Text] [PDF]

				P. A. Mak, H. R. Kast-Woelbern, A. M. Anisfeld, and P. A. Edwards Identification of PLTP as an LXR target gene and apoE as an FXR target gene reveals overlapping targets for the two nuclear receptors J. Lipid Res., December 1, 2002; 43(12): 2037 - 2041. [Abstract] [Full Text] [PDF]

				T. M. Stulnig, K. R. Steffensen, H. Gao, M. Reimers, K. Dahlman-Wright, G. U. Schuster, and J.-A. Gustafsson Novel Roles of Liver X Receptors Exposed by Gene Expression Profiling in Liver and Adipose Tissue Mol. Pharmacol., December 1, 2002; 62(6): 1299 - 1305. [Abstract] [Full Text] [PDF]

				F. Forcheron, A. Cachefo, S. Thevenon, C. Pinteur, and M. Beylot Mechanisms of the Triglyceride- and Cholesterol-Lowering Effect of Fenofibrate in Hyperlipidemic Type 2 Diabetic Patients Diabetes, December 1, 2002; 51(12): 3486 - 3491. [Abstract] [Full Text] [PDF]

				G. Cao, T. P. Beyer, X. P. Yang, R. J. Schmidt, Y. Zhang, W. R. Bensch, R. F. Kauffman, H. Gao, T. P. Ryan, Y. Liang, et al. Phospholipid Transfer Protein Is Regulated by Liver X Receptors in Vivo J. Biol. Chem., October 11, 2002; 277(42): 39561 - 39565. [Abstract] [Full Text] [PDF]

				B. G. Brown, M. C. Cheung, A. C. Lee, X.-Q. Zhao, and A. Chait Antioxidant Vitamins and Lipid Therapy: End of a Long Romance? Arterioscler. Thromb. Vasc. Biol., October 1, 2002; 22(10): 1535 - 1546. [Abstract] [Full Text] [PDF]

				A. Grefhorst, B. M. Elzinga, P. J. Voshol, T. Plosch, T. Kok, V. W. Bloks, F. H. van der Sluijs, L. M. Havekes, J. A. Romijn, H. J. Verkade, et al. Stimulation of Lipogenesis by Pharmacological Activation of the Liver X Receptor Leads to Production of Large, Triglyceride-rich Very Low Density Lipoprotein Particles J. Biol. Chem., September 6, 2002; 277(37): 34182 - 34190. [Abstract] [Full Text] [PDF]

				P. A. Mak, B. A. Laffitte, C. Desrumaux, S. B. Joseph, L. K. Curtiss, D. J. Mangelsdorf, P. Tontonoz, and P. A. Edwards Regulated Expression of the Apolipoprotein E/C-I/C-IV/C-II Gene Cluster in Murine and Human Macrophages. A CRITICAL ROLE FOR NUCLEAR LIVER X RECEPTORS alpha AND beta J. Biol. Chem., August 23, 2002; 277(35): 31900 - 31908. [Abstract] [Full Text] [PDF]

				S. E. Ross, R. L. Erickson, I. Gerin, P. M. DeRose, L. Bajnok, K. A. Longo, D. E. Misek, R. Kuick, S. M. Hanash, K. B. Atkins, et al. Microarray Analyses during Adipogenesis: Understanding the Effects of Wnt Signaling on Adipogenesis and the Roles of Liver X Receptor {alpha} in Adipocyte Metabolism Mol. Cell. Biol., August 15, 2002; 22(16): 5989 - 5999. [Abstract] [Full Text] [PDF]

				J. Y. L. Chiang Bile Acid Regulation of Gene Expression: Roles of Nuclear Hormone Receptors Endocr. Rev., August 1, 2002; 23(4): 443 - 463. [Abstract] [Full Text] [PDF]

				J. R Mead and D. P Ramji The pivotal role of lipoprotein lipase in atherosclerosis Cardiovasc Res, August 1, 2002; 55(2): 261 - 269. [Full Text] [PDF]

				S. B. Joseph, E. McKilligin, L. Pei, M. A. Watson, A. R. Collins, B. A. Laffitte, M. Chen, G. Noh, J. Goodman, G. N. Hagger, et al. Synthetic LXR ligand inhibits the development of atherosclerosis in mice PNAS, May 28, 2002; 99(11): 7604 - 7609. [Abstract] [Full Text] [PDF]

				Y. Zhang and D. J. Mangelsdorf LuXuRies of Lipid Homeostasis: The Unity of Nuclear Hormone Receptors, Transcription Regulation, and Cholesterol Sensing Mol. Interv., April 1, 2002; 2(2): 78 - 87. [Abstract] [Full Text] [PDF]

				P. A. Edwards, H. R. Kast, and A. M. Anisfeld BAREing it all: the adoption of LXR and FXR and their roles in lipid homeostasis J. Lipid Res., January 1, 2002; 43(1): 2 - 12. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) All Versions of this Article: 276/46/43018    most recent M107823200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zhang, Y. Articles by Mangelsdorf, D. J. Search for Related Content PubMed PubMed Citation Articles by Zhang, Y. Articles by Mangelsdorf, D. J. Social Bookmarking                      What's this?