{"doi":"10.1073/pnas.200367697","title":"Control of cellular cholesterol efflux by the nuclear oxysterol receptor LXRα","abstract":"<jats:p>LXRα is a nuclear receptor that has previously been shown to\n regulate the metabolic conversion of cholesterol to bile acids. Here we\n define a role for this transcription factor in the control of cellular\n cholesterol efflux. We demonstrate that retroviral expression of LXRα\n in NIH 3T3 fibroblasts or RAW264.7 macrophages and/or treatment of\n these cells with oxysterol ligands of LXR results in 7- to 30-fold\n induction of the mRNA encoding the putative cholesterol/phospholipid\n transporter ATP-binding cassette (ABC)A1. In contrast, induction of\n ABCA1 mRNA in response to oxysterols is attenuated in cells that\n constitutively express dominant-negative forms of LXRα or LXRβ that\n lack the AF2 transcriptional activation domain. We further demonstrate\n that expression of LXRα in NIH 3T3 fibroblasts and/or treatment of\n these cells with oxysterols is sufficient to stimulate cholesterol\n efflux to extracellular apolipoprotein AI. The ability of oxysterol\n ligands of LXR to stimulate efflux is dramatically reduced in Tangier\n fibroblasts, which carry a loss of function mutation in the ABCA1 gene.\n Taken together, these results indicate that cellular cholesterol efflux\n is controlled, at least in part, at the level of transcription by a\n nuclear receptor–signaling pathway. They suggest a model in which\n activation of LXRs by oxysterols in response to cellular sterol loading\n leads to induction of the ABCA1 transporter and the stimulation of\n lipid efflux to extracellular acceptors. These findings have important\n implications for our understanding of mammalian cholesterol homeostasis\n and suggest new opportunities for pharmacological regulation of\n cellular lipid metabolism.</jats:p>","journal":"Proceedings of the National Academy of Sciences","year":2000,"id":648083,"datarank":15.57081475169506,"base_score":6.907755278982137,"endowment":6.907755278982137,"self_citation_contribution":1.0361632918473207,"citation_network_contribution":14.534651459847739,"self_endowment_contribution":1.0361632918473207,"citer_contribution":14.534651459847739,"corpus_percentile":null,"corpus_rank":null,"citation_count":999,"citer_count":200,"citers_with_citation_signal":200,"citers_with_endowment":200,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1688782,"name":"Bryan A. Laffitte","orcid":null,"position":1,"is_corresponding":false},{"id":469948,"name":"Sean B. Joseph","orcid":"0000-0002-2602-8517","position":2,"is_corresponding":false},{"id":1688787,"name":"Puiying A. Mak","orcid":null,"position":3,"is_corresponding":false},{"id":1688789,"name":"Damien C. Wilpitz","orcid":null,"position":4,"is_corresponding":false},{"id":354826,"name":"Peter A. Edwards","orcid":null,"position":5,"is_corresponding":false},{"id":246036,"name":"Peter Tontonoz","orcid":"0000-0003-1259-0477","position":6,"is_corresponding":false},{"id":1688780,"name":"Asha Venkateswaran","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Control of cellular cholesterol efflux by the nuclear oxysterol receptor LXRα","abstract":"<jats:p>LXRα is a nuclear receptor that has previously been shown to\n regulate the metabolic conversion of cholesterol to bile acids. Here we\n define a role for this transcription factor in the control of cellular\n cholesterol efflux. We demonstrate that retroviral expression of LXRα\n in NIH 3T3 fibroblasts or RAW264.7 macrophages and/or treatment of\n these cells with oxysterol ligands of LXR results in 7- to 30-fold\n induction of the mRNA encoding the putative cholesterol/phospholipid\n transporter ATP-binding cassette (ABC)A1. In contrast, induction of\n ABCA1 mRNA in response to oxysterols is attenuated in cells that\n constitutively express dominant-negative forms of LXRα or LXRβ that\n lack the AF2 transcriptional activation domain. We further demonstrate\n that expression of LXRα in NIH 3T3 fibroblasts and/or treatment of\n these cells with oxysterols is sufficient to stimulate cholesterol\n efflux to extracellular apolipoprotein AI. The ability of oxysterol\n ligands of LXR to stimulate efflux is dramatically reduced in Tangier\n fibroblasts, which carry a loss of function mutation in the ABCA1 gene.\n Taken together, these results indicate that cellular cholesterol efflux\n is controlled, at least in part, at the level of transcription by a\n nuclear receptor–signaling pathway. They suggest a model in which\n activation of LXRs by oxysterols in response to cellular sterol loading\n leads to induction of the ABCA1 transporter and the stimulation of\n lipid efflux to extracellular acceptors. These findings have important\n implications for our understanding of mammalian cholesterol homeostasis\n and suggest new opportunities for pharmacological regulation of\n cellular lipid metabolism.</jats:p>","is_dataset_classified":null,"base_score":6.907755278982137,"endowment":6.907755278982137,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"11035776","pmcid":"PMC17300","openalex_id":"https://openalex.org/W2093296161","authors":[],"funders":[{"funder_name":"NHLBI NIH HHS","grant_id":"HL 30568","title":null},{"funder_name":"NHLBI NIH HHS","grant_id":"P01 HL030568","title":null}],"total_grants":2,"fwci":55.2443,"citation_percentile":0.99954822,"influential_citations":0,"citation_trend":[{"year":2012,"count":43},{"year":2013,"count":44},{"year":2014,"count":43},{"year":2015,"count":45},{"year":2016,"count":27},{"year":2017,"count":29},{"year":2018,"count":28},{"year":2019,"count":44},{"year":2020,"count":39},{"year":2021,"count":34},{"year":2022,"count":28},{"year":2023,"count":27},{"year":2024,"count":25},{"year":2025,"count":23},{"year":2026,"count":12}],"oa_status":"closed","license":null,"oa_locations":[{"url":"https://pnas.org/doi/pdf/10.1073/pnas.200367697","host_type":"publisher"},{"url":"https://doi.org/10.1073/pnas.200367697","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/11035776","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/17300","host_type":"repository"}],"fields_of_study":["Cholesterol and Lipid Metabolism","Drug Transport and Resistance Mechanisms","Peroxisome Proliferator-Activated Receptors","3T3 Cells","Animals","Biological Transport","Cells, Cultured","Cholesterol","DNA-Binding Proteins","Humans","Liver X Receptors","Macrophages","Mice","Monocytes","Orphan Nuclear Receptors","Receptors, Cytoplasmic and Nuclear"],"mesh_terms":["Liver X Receptors","Animals","Biological Transport","Cells, Cultured","Cholesterol","DNA-Binding Proteins","Humans","Macrophages","Monocytes","3T3 Cells","Receptors, Cytoplasmic and Nuclear","Mice","Orphan Nuclear Receptors"],"keywords":["ABCA1","Liver X receptor","Oxysterol","ATP Binding Cassette Transporter 1","Biology","Cholesterol","Reverse cholesterol transport","Cell biology","Nuclear receptor","Transcription factor","Efflux","Biochemistry","Transporter","Lipoprotein"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-10T02:12:55.740992Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}