RESUMEN
Liver X receptors (LXRs) are nuclear transcription factors important in the regulation of cholesterol transport, and glucose and fatty acid metabolism. The antiproliferative role of LXRs has been studied in a variety of malignancies and may represent a therapeutic opportunity in cancers lacking targeted therapies, such as triple-negative breast cancer. In this study, we investigated the impact of LXR agonists alone and in combination with carboplatin in preclinical models of breast cancer. In vitro experiments revealed a dose-dependent decrease in tumor cell proliferation in estrogen receptor-positive breast cancer cells, whereas LXR activation in vivo resulted in an increased growth inhibitory effect in a basal-like breast cancer model (in combination with carboplatin). Functional proteomic analysis identified differences in protein expression between responding and nonresponding models related to Akt activity, cell-cycle progression, and DNA repair. Furthermore, pathway analysis suggested that the LXR agonist in combination with carboplatin inhibits the activity of targets of E2F transcription factors and affects cholesterol homeostasis in basal-like breast cancer.
Asunto(s)
Neoplasias de la Mama , Receptores Nucleares Huérfanos , Humanos , Femenino , Receptores X del Hígado/metabolismo , Receptores Nucleares Huérfanos/metabolismo , Neoplasias de la Mama/patología , Carboplatino/metabolismo , Proteómica , Colesterol/metabolismo , Hígado/patologíaRESUMEN
The synchronization of circadian clock depends on a central pacemaker located in the suprachiasmatic nuclei. However, the potential feedback of peripheral signals on the central clock remains poorly characterized. To explore whether peripheral organ circadian clocks may affect the central pacemaker, we used a chimeric model in which mouse hepatocytes were replaced by human hepatocytes. Liver humanization led to reprogrammed diurnal gene expression and advanced the phase of the liver circadian clock that extended to muscle and the entire rhythmic physiology. Similar to clock-deficient mice, liver-humanized mice shifted their rhythmic physiology more rapidly to the light phase under day feeding. Our results indicate that hepatocyte clocks can affect the central pacemaker and offer potential perspectives to apprehend pathologies associated with altered circadian physiology.
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Relojes Circadianos , Ritmo Circadiano , Humanos , Ratones , Animales , Ritmo Circadiano/genética , Hígado/metabolismo , Hepatocitos , Relojes Circadianos/genética , Núcleo Supraquiasmático/metabolismoRESUMEN
BACKGROUND: Sterol O-acyltransferase 2 (Soat2) encodes acyl-coenzyme A:cholesterol acyltransferase 2 (ACAT2), which synthesizes cholesteryl esters in hepatocytes and enterocytes fated either to storage or to secretion into nascent triglyceride-rich lipoproteins. OBJECTIVES: We aimed to unravel the molecular mechanisms leading to reduced hepatic steatosis when Soat2 is depleted in mice. METHODS: Soat2-/- and wild-type mice were fed a high-fat, a high-carbohydrate, or a chow diet, and parameters of lipid and glucose metabolism were assessed. RESULTS: Glucose, insulin, homeostatic model assessment for insulin resistance (HOMA-IR), oral glucose tolerance (OGTT), and insulin tolerance tests significantly improved in Soat2-/- mice, irrespective of the dietary regimes (2-way ANOVA). The significant positive correlations between area under the curve (AUC) OGTT (r = 0.66, p < 0.05), serum fasting insulin (r = 0.86, p < 0.05), HOMA-IR (r = 0.86, p < 0.05), Adipo-IR (0.87, p < 0.05), hepatic triglycerides (TGs) (r = 0.89, p < 0.05), very-low-density lipoprotein (VLDL)-TG (r = 0.87, p < 0.05) and the hepatic cholesteryl esters in wild-type mice disappeared in Soat2-/- mice. Genetic depletion of Soat2 also increased whole-body oxidation by 30% (p < 0.05) compared to wild-type mice. CONCLUSION: Our data demonstrate that ACAT2-generated cholesteryl esters negatively affect the metabolic control by retaining TG in the liver and that genetic inhibition of Soat2 improves liver steatosis via partitioning of lipids into secretory (VLDL-TG) and oxidative (fatty acids) pathways.
Asunto(s)
Hígado Graso , Insulinas , Esterol O-Aciltransferasa , Animales , Ésteres del Colesterol/metabolismo , Hígado Graso/metabolismo , Glucosa/metabolismo , Insulinas/metabolismo , Lipoproteínas VLDL/metabolismo , Hígado/metabolismo , Masculino , Ratones , Ratones Noqueados , Esterol O-Aciltransferasa/genética , Esterol O-Aciltransferasa/metabolismo , Triglicéridos , Esterol O-Aciltransferasa 2RESUMEN
BACKGROUND AND AIMS: Genetically modified mice have been used extensively to study human disease. However, the data gained are not always translatable to humans because of major species differences. Liver-humanized mice (LHM) are considered a promising model to study human hepatic and systemic metabolism. Therefore, we aimed to further explore their lipoprotein metabolism and to characterize key hepatic species-related, physiological differences. APPROACH AND RESULTS: Fah-/- , Rag2-/- , and Il2rg-/- knockout mice on the nonobese diabetic (FRGN) background were repopulated with primary human hepatocytes from different donors. Cholesterol lipoprotein profiles of LHM showed a human-like pattern, characterized by a high ratio of low-density lipoprotein to high-density lipoprotein, and dependency on the human donor. This pattern was determined by a higher level of apolipoprotein B100 in circulation, as a result of lower hepatic mRNA editing and low-density lipoprotein receptor expression, and higher levels of circulating proprotein convertase subtilisin/kexin type 9. As a consequence, LHM lipoproteins bind to human aortic proteoglycans in a pattern similar to human lipoproteins. Unexpectedly, cholesteryl ester transfer protein was not required to determine the human-like cholesterol lipoprotein profile. Moreover, LHM treated with GW3965 mimicked the negative lipid outcomes of the first human trial of liver X receptor stimulation (i.e., a dramatic increase of cholesterol and triglycerides in circulation). Innovatively, LHM allowed the characterization of these effects at a molecular level. CONCLUSIONS: LHM represent an interesting translatable model of human hepatic and lipoprotein metabolism. Because several metabolic parameters displayed donor dependency, LHM may also be used in studies for personalized medicine.
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Benzoatos/farmacocinética , Bencilaminas/farmacocinética , Colesterol/metabolismo , Hepatocitos/metabolismo , Lipoproteínas/metabolismo , Receptores X del Hígado/agonistas , Hígado/metabolismo , Animales , Hepatocitos/trasplante , Humanos , Hígado/cirugía , Masculino , Ratones , Ratones NoqueadosRESUMEN
Obesity triggers the development of non-alcoholic fatty liver disease (NAFLD), which involves alterations of regulatory transcription networks and epigenomes in hepatocytes. Here we demonstrate that G protein pathway suppressor 2 (GPS2), a subunit of the nuclear receptor corepressor (NCOR) and histone deacetylase 3 (HDAC3) complex, has a central role in these alterations and accelerates the progression of NAFLD towards non-alcoholic steatohepatitis (NASH). Hepatocyte-specific Gps2 knockout in mice alleviates the development of diet-induced steatosis and fibrosis and causes activation of lipid catabolic genes. Integrative cistrome, epigenome and transcriptome analysis identifies the lipid-sensing peroxisome proliferator-activated receptor α (PPARα, NR1C1) as a direct GPS2 target. Liver gene expression data from human patients reveal that Gps2 expression positively correlates with a NASH/fibrosis gene signature. Collectively, our data suggest that the GPS2-PPARα partnership in hepatocytes coordinates the progression of NAFLD in mice and in humans and thus might be of therapeutic interest.
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Péptidos y Proteínas de Señalización Intracelular/metabolismo , Hígado/patología , Enfermedad del Hígado Graso no Alcohólico/patología , PPAR alfa/metabolismo , Animales , Biopsia , Conjuntos de Datos como Asunto , Dieta Alta en Grasa/efectos adversos , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Epigénesis Genética , Fibrosis , Células HEK293 , Hepatocitos/metabolismo , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Metabolismo de los Lípidos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Enfermedad del Hígado Graso no Alcohólico/etiología , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/metabolismo , PPAR alfa/genéticaRESUMEN
Thyroid hormones have important effects on cellular development, growth, and metabolism and are necessary for the healthy function of almost all tissues. Hyperthyroid patients with excess thyroid hormone levels experience tachycardia, fatigue, muscle wasting, and osteoporosis. However, although high thyroid hormone levels have adverse effects, efforts have been made to harness the beneficial effects, such as reduced serum low-density lipoprotein (LDL) cholesterol levels, elevated basal metabolic rate, and weight loss. Thyroid hormones interact with nuclear thyroid hormone receptors (TRs), and cholesterol levels are reduced through TRß, whereas extrahepatic adverse actions are primarily connected to TRα. Thus, to develop a useful compound for clinical use, efforts have been focusing on developing compounds with isomer-specific functions based on the structure of thyroid hormones, i.e., thyromimetics that are liver and/or TRß specific. In this short review, we discuss the development of the early thyromimetics that enabled, through modern molecular techniques, the progress towards improved design of TRß-selective thyromimetics. We also address the early promise shown in human clinical trials and the current status of these drugs and other emerging compounds.
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Hiperlipidemias/tratamiento farmacológico , Receptores beta de Hormona Tiroidea/agonistas , Hormonas Tiroideas/farmacología , Animales , Colesterol/metabolismo , Diseño de Fármacos , Humanos , Hiperlipidemias/metabolismo , Hígado/metabolismoRESUMEN
Hepatitis C virus (HCV) is an enveloped RNA virus responsible for 170 million cases of viral hepatitis worldwide. Over 50% of chronically infected HCV patients develop hepatic steatosis, and steatosis can be induced by expression of HCV core protein (core) alone. Additionally, core must associate with cytoplasmic lipid droplets (LDs) for steatosis development and viral particle assembly. Due to the importance of the LD as a key component of hepatic lipid storage and as a platform for HCV particle assembly, it seems this dynamic subcellular organelle is a gatekeeper in the pathogenesis of viral hepatitis. Here, we hypothesized that core requires the host LD scaffold protein, perilipin (PLIN)3, to induce hepatic steatosis. To test our hypothesis in vivo, we have studied core-induced hepatic steatosis in the absence or presence of antisense oligonucleotide-mediated knockdown of PLIN3. PLIN3 knockdown blunted HCV core-induced steatosis in transgenic mice fed either chow or a moderate fat diet. Collectively, our studies demonstrate that the LD scaffold protein, PLIN3, is essential for HCV core-induced hepatic steatosis and provide new insights into the pathogenesis of HCV.
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Hígado Graso/genética , Hepatitis C/metabolismo , Hígado/metabolismo , Perilipina-3/genética , Animales , Hígado Graso/metabolismo , Hígado Graso/patología , Técnicas de Silenciamiento del Gen , Genotipo , Hepacivirus , Hepatitis C/genética , Hepatitis C/patología , Hepatitis C/virología , Humanos , Gotas Lipídicas/metabolismo , Gotas Lipídicas/patología , Gotas Lipídicas/virología , Metabolismo de los Lípidos/genética , Hígado/patología , Hígado/virología , Ratones , Oligonucleótidos Antisentido/administración & dosificación , Oligonucleótidos Antisentido/genética , Perilipina-3/antagonistas & inhibidoresRESUMEN
INTRODUCTION: Liver X receptors (LXRs) are nuclear receptors with well-known functions in cholesterol transport, fatty acid and glucose metabolism, and modulation of immune responses. Natural and synthetic ligands have been identified and are under development for the treatment of metabolic and inflammatory conditions and diseases. There is mounting evidence pointing to functional roles for LXRs in a variety of malignancies and the potential therapeutic efficacy of their ligands. AREAS COVERED: This review summarizes the discovery and characterization of LXRs and their ligands, surveys their effects and mechanisms of action in cell-based and animal models of cancer, and proposes the future direction of basic and translational studies of LXRs and their ligands in cancer research and therapeutics. EXPERT OPINION: Targeting LXRs is a promising strategy for cancer treatment, particularly for those cancers which do not have effective treatment options. Key questions remain, however, regarding the specific mechanisms of action, effects on other target cells within the tumor microenvironment, and receptor status in patient populations. Moreover, LXR ligands optimized for disease-specific functions and cancer-related endpoints are currently not available. These issues represent both challenges and significant opportunities for future research and development efforts.
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Antineoplásicos/farmacología , Neoplasias/tratamiento farmacológico , Receptores Nucleares Huérfanos/metabolismo , Animales , Modelos Animales de Enfermedad , Diseño de Fármacos , Humanos , Ligandos , Receptores X del Hígado , Terapia Molecular Dirigida , Neoplasias/patología , Microambiente Tumoral/efectos de los fármacosRESUMEN
Pancreatic ductal adenocarcinoma (PDAC) is difficult to detect early and is often resistant to standard chemotherapeutic options, contributing to extremely poor disease outcomes. Members of the nuclear receptor superfamily carry out essential biological functions such as hormone signaling and are successfully targeted in the treatment of endocrine-related malignancies. Liver X receptors (LXRs) are nuclear receptors that regulate cholesterol homeostasis, lipid metabolism, and inflammation, and LXR agonists have been developed to regulate LXR function in these processes. Intriguingly, these compounds also exhibit antiproliferative activity in diverse types of cancer cells. In this study, LXR agonist treatments disrupted proliferation, cell-cycle progression, and colony-formation of PDAC cells. At the molecular level, treatments downregulated expression of proteins involved in cell cycle progression and growth factor signaling. Microarray experiments further revealed changes in expression profiles of multiple gene networks involved in biological processes and pathways essential for cell growth and proliferation following LXR activation. These results establish the antiproliferative effects of LXR agonists and potential mechanisms of action in PDAC cells and provide evidence for their potential application in the prevention and treatment of PDAC.
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Antineoplásicos/farmacología , Benzoatos/farmacología , Bencilaminas/farmacología , Regulación Neoplásica de la Expresión Génica , Proteínas de Neoplasias/genética , Receptores Nucleares Huérfanos/genética , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Adulto , Anciano , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacología , Femenino , Perfilación de la Expresión Génica , Humanos , Ligandos , Receptores X del Hígado , Masculino , Análisis por Micromatrices , Persona de Mediana Edad , Proteínas de Neoplasias/metabolismo , Receptores Nucleares Huérfanos/agonistas , Receptores Nucleares Huérfanos/metabolismo , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Transducción de Señal , GemcitabinaRESUMEN
UNLABELLED: Liver X receptor (LXR) activation stimulates triglyceride (TG) accumulation in the liver. Several lines of evidence indicate that estradiol-17ß (E2) reduces TG levels in the liver; however, the molecular mechanism underlying the E2 effect remains unclear. Here, we show that administration of E2 attenuated sterol regulatory element-binding protein (SREBP)-1 expression and TG accumulation induced by LXR activation in mouse liver. In estrogen receptor alpha (ERα) knockout (KO) and liver-specific ERα KO mice, E2 did not affect SREBP-1 expression or TG levels. Molecular analysis revealed that ERα is recruited to the SREBP-1c promoter through direct binding to LXR and inhibits coactivator recruitment to LXR in an E2-dependent manner. Our findings demonstrate the existence of a novel liver-dependent mechanism controlling TG accumulation through the nonclassical ER/LXR pathway. To confirm that a nonclassical ER/LXR pathway regulates ERα-dependent inhibition of LXR activation, we screened ERα ligands that were able to repress LXR activation without enhancing ERα transcriptional activity, and, as a result, we identified the phytoestrogen, phloretin. In mice, phloretin showed no estrogenic activity; however, it did reduce SREBP-1 expression and TG levels in liver of mice fed a high-fat diet to an extent similar to that of E2. CONCLUSION: We propose that ER ligands reduce TG levels in the liver by inhibiting LXR activation through a nonclassical pathway. Our results also indicate that the effects of ER on TG accumulation can be distinguished from its estrogenic effects by a specific ER ligand.
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Hígado Graso/prevención & control , Receptores Nucleares Huérfanos/fisiología , Receptores de Estrógenos/fisiología , Animales , Dieta Alta en Grasa , Estradiol/farmacología , Femenino , Ligandos , Receptores X del Hígado , Ratones , Ratones Endogámicos C57BL , Receptores Nucleares Huérfanos/antagonistas & inhibidores , Floretina/farmacología , Regiones Promotoras Genéticas , Transducción de Señal , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/genética , Activación Transcripcional , Triglicéridos/metabolismoRESUMEN
INTRODUCTION: Liver × receptors (LXRs) are members of the nuclear receptor family of ligand-dependent transcription factors and have established functions as regulators of cholesterol, glucose, and fatty acid metabolism and inflammatory responses. Published reports of anti-proliferative effects of synthetic LXR ligands on breast, prostate, ovarian, lung, skin, and colorectal cancer cells suggest that LXRs are potential targets in cancer prevention and treatment. METHODS: To further determine the effects of LXR ligands and identify their potential mechanisms of action in breast cancer cells, we carried out microarray analysis of gene expression in four breast cancer cell lines following treatments with the synthetic LXR ligand GW3965. Differentially expressed genes were further subjected to gene ontology and pathway analyses, and their expression profiles and associations with disease parameters and outcomes were examined in clinical samples. Response of E2F target genes were validated by real-time PCR, and the posited role of E2F2 in breast cancer cell proliferation was tested by RNA interference experiments. RESULTS: We observed cell line-specific transcriptional responses as well as a set of common responsive genes. In the common responsive gene set, upregulated genes tend to function in the known metabolic effects of LXR ligands and LXRs whereas the downregulated genes mostly include those which function in cell cycle regulation, DNA replication, and other cell proliferation-related processes. Transcription factor binding site analysis of the downregulated genes revealed an enrichment of E2F binding site sequence motifs. Correspondingly, E2F2 transcript levels are downregulated following LXR ligand treatment. Knockdown of E2F2 expression, similar to LXR ligand treatment, resulted in a significant disruption of estrogen receptor positive breast cancer cell proliferation. Ligand treatment also decreased E2F2 binding to cis-regulatory regions of target genes. Hierarchical clustering of breast cancer patients based on the expression profiles of the commonly downregulated LXR ligand-responsive genes showed a strong association of these genes with patient survival. CONCLUSIONS: Taken together, these results indicate that LXR ligands target gene networks, including those regulated by E2F family members, are critical for tumor biology and disease progression and merit further consideration as potential agents in the prevention and treatment of breast cancers.
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Benzoatos/metabolismo , Bencilaminas/metabolismo , Neoplasias de la Mama/genética , Factor de Transcripción E2F2/biosíntesis , Receptores Nucleares Huérfanos/metabolismo , Benzoatos/administración & dosificación , Bencilaminas/administración & dosificación , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Factor de Transcripción E2F2/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Ligandos , Receptores X del Hígado , Regiones Promotoras Genéticas , Transcripción Genética/efectos de los fármacosRESUMEN
The oxysterol receptors LXRα and LXRß are members of the nuclear receptor family and established transcriptional regulators of lipid metabolism with additional anti-inflammatory functions. Recent investigations have indicated an important role of LXRs in the control of proliferation. Here we further extend this knowledge to human colon cancer cells and proliferation in mouse colon. We show that activation of LXRs leads to a robust cell cycle arrest in colorectal adenocarcinoma cell lines. At the molecular level LXRs control expression of several cell cycle genes including Skp2, c-Myc, CDKs, cyclins, and p15. Furthermore, activation of LXRs causes hypo-phosphorylation of the retinoblastoma (Rb) tumor suppressor protein. Experiments performed in vivo show that the colon structure appears to be intact in LXR null mice. However, LXRαß(-/-) mice show a significant increase of proliferation markers in colon compared to wild type mice and administration of the LXR specific agonist, GW3965 significantly reduced expression of proliferation in mouse colon. Taken together, these findings point toward a strong anti-proliferative effect of LXRs in colon revealing the potential of LXR ligands as possible anti cancer agents.
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Proliferación Celular , Colon/metabolismo , Colon/patología , Neoplasias del Colon/metabolismo , Neoplasias del Colon/patología , Receptores Nucleares Huérfanos/metabolismo , Animales , Ciclo Celular , Línea Celular Tumoral , Colon/citología , Regulación de la Expresión Génica , Humanos , Receptores X del Hígado , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores Nucleares Huérfanos/análisis , Receptores Nucleares Huérfanos/genéticaRESUMEN
The orphan nuclear receptor Steroidogenic Factor-1 (SF-1, NR5A1) is a critical regulator of development and homeostasis of the adrenal cortex and gonads. We recently showed that a complex containing E3 ubiquitin ligase RNF31 and the known SF-1 corepressor DAX-1 (NR0B1) interacts with SF-1 on target promoters and represses transcription of steroidogenic acute regulatory protein (StAR) and aromatase (CYP19) genes. To further evaluate the role of SF-1 in the adrenal cortex and the involvement of RNF31 in SF-1-dependent pathways, we performed genome-wide gene-expression analysis of adrenocortical NCI-H295R cells where SF-1 or RNF31 had been knocked down using RNA interference. We find RNF31 to be deeply connected to cholesterol metabolism and steroid hormone synthesis, strengthening its role as an SF-1 coregulator. We also find intriguing evidence of negative crosstalk between SF-1 and both transforming growth factor (TGF) ß and Wnt/ß-catenin signaling. This crosstalk could be of importance for adrenogonadal development, maintenance of adrenocortical progenitor cells and the development of adrenocortical carcinoma. Finally, the SF-1 gene profile can be used to distinguish malignant from benign adrenocortical tumors, a finding that implicates SF-1 in the development of malignant adrenocortical carcinoma.
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Corteza Suprarrenal/metabolismo , Carcinoma Corticosuprarrenal/metabolismo , Proteínas Portadoras/metabolismo , Regulación de la Expresión Génica/fisiología , Factor Esteroidogénico 1/metabolismo , Vía de Señalización Wnt/fisiología , Western Blotting , Bromodesoxiuridina , Proteínas Portadoras/genética , Línea Celular Tumoral , Colforsina , Biología Computacional , Regulación de la Expresión Génica/genética , Técnicas de Silenciamiento del Gen/métodos , Hormonas Esteroides Gonadales/biosíntesis , Humanos , Análisis por Micromatrices , Reacción en Cadena de la Polimerasa , ARN Interferente Pequeño/genética , Factor Esteroidogénico 1/genética , Factor de Crecimiento Transformador beta/metabolismo , Ubiquitina-Proteína Ligasas , beta Catenina/metabolismoRESUMEN
The oxysterol receptors [liver X receptors (LXRalpha and LXRbeta)] regulate cholesterol and lipid biosynthesis and several studies link dysregulation of these metabolic pathways to aberrant cell growth. Here, we show that activation of LXR significantly reduced proliferation in several human breast cancer cells lines. LXR suppressed messenger RNA and/or protein expression of Skp2, cyclin A2, cyclin D1 and estrogen receptor (ER) alpha, whereas it increased the expression of p53 at the protein level and maintained the retinoblastoma protein in a hypophosphorylated active form. These changes may constitute part of the molecular mechanisms behind the antiproliferative effect of LXR. Furthermore, activation of LXR induced expression of key lipogenic genes including sterol regulatory element-binding protein 1c (SREBP1c), fatty acid synthase and stearoyl-coenzyme A desaturase 1, leading to increased triglyceride production in MCF7 cells. Small interfering RNA knockdown of SREBP1c, a master regulator of the lipid biosynthesis, did not abolish the antiproliferative effect of LXR in these cells. Combined these studies identify LXRs as both antiproliferative and lipogenic factors in breast cancer cells and indicate that the antiproliferative effect of LXRs is independent of lipid biosynthesis.