{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T19:39:52Z","timestamp":1785872392509,"version":"3.56.0"},"reference-count":29,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2019,5,22]],"date-time":"2019-05-22T00:00:00Z","timestamp":1558483200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2019,5,22]],"date-time":"2019-05-22T00:00:00Z","timestamp":1558483200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Genome-wide association studies (GWAS) have identified many genetic variants in genes related to lipid metabolism. However, how these variations affect lipid levels remains elusive. Long non-coding RNAs (lncRNAs) have been implicated in a variety of biological processes. We hypothesize lncRNAs are likely to be located within disease or trait-associated DNA regions to regulate lipid metabolism. The aim of this study was to investigate whether and how lncRNAs in lipid- associated DNA regions regulate cholesterol homeostasis in hepatocytes. In this study, we identified a novel long non-coding RNA in Lipid Associated Single nucleotide polymorphism gEne Region (LASER) by bioinformatic analysis. We report that LASER is highly expressed in both hepatocytes and peripheral mononuclear cells (PBMCs). Clinical studies showed that LASER expression is positively related with that of cholesterol containing apolipoprotein levels. In particular, we found that LASER is positively correlated with plasma PCSK9 levels in statin free patients. siRNAs mediated knock down of LASER dramatically reduces intracellular cholesterol levels and affects the expression of genes involved in cholesterol metabolism. Transcriptome analyses show that knockdown of LASER affects the expression of genes involved in metabolism pathways. We found that HNF-1\u03b1 and PCSK9 were reduced after LASER knock-down. Interestingly, the reduction of PCSK9 can be blocked by the treatment of berberine, a natural cholesterol-lowering compound which functions as a HNF-1\u03b1 antagonist. Mechanistically, we found that LASER binds to LSD1 (lysine-specific demethylase 1), a member of CoREST\/REST complex, in nucleus. LASER knock-down enhance LSD1 targeting to genomic loci, resulting in decreased histone H3 lysine 4 mono-methylation at the promoter regions of HNF-1\u03b1 gene. Conversely, LSD1 knock-down abolished the effect of LASER on HNF-1\u03b1 and PCSK9 expressions. Finally, we found that statin treatment increased LASER expression, accompanied with increased PCSK9 expression, suggesting a feedback regulation of cholesterol on LASER expression. This observation may partly explain the statin escape during anti-cholesterol treatment. These findings identified a novel lncRNA in cholesterol homeostasis. Therapeutic targeting LASER might be an effective approach to augment the effect of statins on cholesterol levels in clinics.<\/jats:p>","DOI":"10.1038\/s41598-019-44195-2","type":"journal-article","created":{"date-parts":[[2019,5,22]],"date-time":"2019-05-22T10:04:48Z","timestamp":1558519488000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Regulation of Cholesterol Homeostasis by a Novel Long Non-coding RNA LASER"],"prefix":"10.1038","volume":"9","author":[{"given":"Chuanwei","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhangxue","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junyi","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zaicheng","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoli","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yukai","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caiyu","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Cai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuewei","family":"Xia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoqun","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Da-zhi","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gengze","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunyu","family":"Zeng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,5,22]]},"reference":[{"key":"44195_CR1","doi-asserted-by":"publisher","first-page":"1483","DOI":"10.1161\/CIRCULATIONAHA.113.004042","volume":"129","author":"AE Moran","year":"2014","unstructured":"Moran, A. E. et al. Temporal trends in ischemic heart disease mortality in 21 world regions, 1980 to 2010: the Global Burden of Disease 2010 study. Circulation. 129, 1483\u201392 (2014).","journal-title":"Circulation."},{"key":"44195_CR2","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1038\/ng.76","volume":"40","author":"CJ Willer","year":"2008","unstructured":"Willer, C. J. et al. Newly identified loci that influence lipid concentrations and risk of coronary artery disease. Nat Genet. 40, 161\u20139 (2008).","journal-title":"Nat Genet."},{"key":"44195_CR3","doi-asserted-by":"publisher","first-page":"707","DOI":"10.1038\/nature09270","volume":"466","author":"TM Teslovich","year":"2010","unstructured":"Teslovich, T. M. et al. Biological, clinical and population relevance of 95 loci for blood lipids. Nature. 466, 707\u201313 (2010).","journal-title":"Nature."},{"key":"44195_CR4","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1038\/ng.269","volume":"41","author":"YS Aulchenko","year":"2009","unstructured":"Aulchenko, Y. S. et al. Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts. Nat Genet. 41, 47\u201355 (2009).","journal-title":"Nat Genet."},{"key":"44195_CR5","doi-asserted-by":"publisher","first-page":"326ra22","DOI":"10.1126\/scitranslmed.aaf1475","volume":"8","author":"J Viereck","year":"2016","unstructured":"Viereck, J. et al. Long noncoding RNA Chast promotes cardiac remodeling. Sci Transl Med. 8, 326ra22 (2016).","journal-title":"Sci Transl Med."},{"key":"44195_CR6","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1126\/science.aad0467","volume":"352","author":"A Castellanos-Rubio","year":"2016","unstructured":"Castellanos-Rubio, A. et al. A long noncoding RNA associated with susceptibility to celiac disease. Scienc. 352, 91\u20135 (2016).","journal-title":"Scienc."},{"key":"44195_CR7","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1016\/j.cellimm.2014.03.015","volume":"289","author":"D Chen","year":"2014","unstructured":"Chen, D. et al. ANRIL inhibits p15(INK4b) through the TGF\u03b21 signaling pathway in human esophageal squamous cell carcinoma. Cell Immunol. 289, 91\u20136 (2014).","journal-title":"Cell Immunol."},{"key":"44195_CR8","doi-asserted-by":"publisher","first-page":"e000884","DOI":"10.1161\/JAHA.114.000884","volume":"3","author":"A Douvris","year":"2014","unstructured":"Douvris, A. et al. Functional analysis of the TRIB1 associated locus linked to plasma triglycerides and coronary artery disease. J Am Heart Assoc. 3, e000884 (2014).","journal-title":"J Am Heart Assoc."},{"key":"44195_CR9","doi-asserted-by":"publisher","first-page":"1262","DOI":"10.1172\/JCI61919","volume":"122","author":"D Ai","year":"2012","unstructured":"Ai, D. et al. Regulation of hepatic LDL receptors by mTORC1 and PCSK9 in mice. J Clin Invest. 122, 1262\u201370 (2012).","journal-title":"J Clin Invest."},{"key":"44195_CR10","doi-asserted-by":"crossref","first-page":"e001937","DOI":"10.1161\/JAHA.115.001937","volume":"4","author":"C Li","year":"2015","unstructured":"Li, C. et al. Efficiency and safety of Proprotein Convertase Subtilisin\/Kexin 9 monoclonal antibody on hypercholesterolemia: A meta-analysis of 20 randomized controlled trials. J Am Heart Assoc. 4, e001937 (2015).","journal-title":"J Am Heart Assoc."},{"key":"44195_CR11","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1007\/s00395-015-0463-z","volume":"110","author":"R Schulz","year":"2015","unstructured":"Schulz, R., Schl\u00fcter, K. D. & Laufsm, U. Molecular and cellular function of the proprotein convertase subtilisin\/kexin type 9 (PCSK9). Basic Res Cardiol. 110, 4 (2015).","journal-title":"Basic Res Cardiol."},{"key":"44195_CR12","doi-asserted-by":"publisher","first-page":"4047","DOI":"10.1074\/jbc.M114.597229","volume":"290","author":"B Dong","year":"2015","unstructured":"Dong, B., Li, H., Singh, A. B., Cao, A. & Liu, J. Inhibition of PCSK9 transcription by berberine involves down-regulation of hepatic HNF1\u03b1 protein expression through the ubiquitin-proteasome degradation pathway. J Biol Chem. 290, 4047\u201358 (2015).","journal-title":"J Biol Chem."},{"key":"44195_CR13","doi-asserted-by":"publisher","first-page":"689","DOI":"10.1126\/science.1192002","volume":"329","author":"MC Tsai","year":"2010","unstructured":"Tsai, M. C. et al. Long noncoding RNA as modular scaffold of histone modification complexes. Science. 329, 689\u201393 (2010).","journal-title":"Science."},{"key":"44195_CR14","doi-asserted-by":"publisher","first-page":"444","DOI":"10.1038\/nmeth.1611","volume":"8","author":"M Bellucci","year":"2011","unstructured":"Bellucci, M., Agostini, F., Masin, M. & Tartaglia, G. G. Predicting protein associations with long noncoding RNAs. Nat Methods. 8, 444\u2013445 (2011).","journal-title":"Nat Methods."},{"key":"44195_CR15","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1016\/j.atherosclerosis.2015.07.012","volume":"242","author":"T Ota","year":"2015","unstructured":"Ota, T. et al. Impact of the statin escape phenomenon on long-term clinical outcomes in patients with acute myocardial infarction: Subgroup analysis of the Nagoya Acute Myocardial Infarction Study (NAMIS). Atherosclerosis. 242, 155\u201360 (2015).","journal-title":"Atherosclerosis."},{"key":"44195_CR16","doi-asserted-by":"publisher","first-page":"6423","DOI":"10.1093\/nar\/gkw341","volume":"44","author":"W Qin","year":"2016","unstructured":"Qin, W. et al. A long non-coding RNA, APOA4-AS, regulates APOA4 expression depending on HuR in mice. Nucleic Acids Res. 44, 6423\u201333 (2016).","journal-title":"Nucleic Acids Res."},{"key":"44195_CR17","doi-asserted-by":"publisher","first-page":"222","DOI":"10.1016\/j.celrep.2013.12.015","volume":"6","author":"P Halley","year":"2014","unstructured":"Halley, P. et al. Regulation of the apolipoprotein gene cluster by a Long noncoding RNA. Cell Rep. 6, 222\u201330 (2014).","journal-title":"Cell Rep."},{"key":"44195_CR18","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1016\/j.cmet.2015.02.004","volume":"21","author":"P Li","year":"2015","unstructured":"Li, P. et al. A liver-enriched long non-coding RNA, lncLSTR, regulates systemic lipid metabolism in mice. Cell Metab. 21, 455\u201367 (2015).","journal-title":"Cell Metab."},{"key":"44195_CR19","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1002\/hep.28391","volume":"64","author":"X Lan","year":"2016","unstructured":"Lan, X. et al. A novel long noncoding RNA Lnc-HC binds hnRNPA2B1 to regulate expressions of Cyp7a1 and Abca1 in hepatocytic cholesterol metabolism. Hepatology. 64, 58\u201372 (2016).","journal-title":"Hepatology."},{"key":"44195_CR20","doi-asserted-by":"publisher","first-page":"124","DOI":"10.1038\/nature17674","volume":"34","author":"T Sallam","year":"2016","unstructured":"Sallam, T. et al. Feedback modulation of cholesterol metabolism by the lipid-responsive non-coding RNA LeXis. Nature. 34, 124\u20138 (2016).","journal-title":"Nature."},{"key":"44195_CR21","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1161\/CIRCGENETICS.115.001274","volume":"9","author":"K Mitchel","year":"2016","unstructured":"Mitchel, K. et al. RP1-13D10.2 is a novel modulator of statin-induced changes in cholesterol. Circ Cardiovasc Genet. 9, 223\u201330 (2016).","journal-title":"Circ Cardiovasc Genet."},{"key":"44195_CR22","doi-asserted-by":"publisher","first-page":"239","DOI":"10.1038\/nature19346","volume":"537","author":"JJ Kotzin","year":"2016","unstructured":"Kotzin, J. J. et al. The long non-coding RNA Morrbid regulates Bim and short-livedmyeloid cell lifespan. Nature. 537, 239\u2013243 (2016).","journal-title":"Nature."},{"key":"44195_CR23","doi-asserted-by":"publisher","first-page":"2752","DOI":"10.1073\/pnas.1419468112","volume":"112","author":"S Pilotto","year":"2015","unstructured":"Pilotto, S. et al. Interplay among nucleosomal DNA, histone tails, and corepressor CoREST underlies LSD1-mediated H3 demethylation. Proc Natl Acad Sci USA 112, 2752\u20137 (2015).","journal-title":"Proc Natl Acad Sci USA"},{"key":"44195_CR24","doi-asserted-by":"publisher","DOI":"10.1038\/srep29142","volume":"6","author":"C Li","year":"2016","unstructured":"Li, C. et al. Zonulin regulates intestinal permeability and facilitates enteric bacteria permeation in coronary artery disease. Sci Rep. 6, 29142 (2016).","journal-title":"Sci Rep."},{"key":"44195_CR25","doi-asserted-by":"publisher","first-page":"1452","DOI":"10.1161\/CIRCULATIONAHA.114.011675","volume":"130","author":"G Wu","year":"2014","unstructured":"Wu, G. et al. LincRNA-p21 regulates neointima formation, vascular smooth muscle cell proliferation, apoptosis, and atherosclerosis by enhancing p53 activity. Circulation. 130, 1452\u20131465 (2014).","journal-title":"Circulation."},{"issue":"1","key":"44195_CR26","doi-asserted-by":"publisher","first-page":"152","DOI":"10.1186\/1471-2105-15-152","volume":"15","author":"Shangwei Ning","year":"2014","unstructured":"Ning, S. et al. LincSNP: a database of linking disease-associated SNPs to human large intergenic non-coding RNAs. BMC Bioinformatics. 2014, 15:152.","journal-title":"BMC Bioinformatics"},{"key":"44195_CR27","doi-asserted-by":"publisher","first-page":"e74","DOI":"10.1093\/nar\/gkt006","volume":"41","author":"L Wang","year":"2013","unstructured":"Wang, L. et al. CPAT: Coding-Potential assessment tool using an alignment-free logistic regression model. Nucleic Acids Res. 41, e74 (2013).","journal-title":"Nucleic Acids Res."},{"issue":"Web Server issu","key":"44195_CR28","doi-asserted-by":"publisher","first-page":"W12","DOI":"10.1093\/nar\/gkx428","volume":"45","author":"Y Kang","year":"2017","unstructured":"Kang, Y. et al. CPC2: a fast and accurate coding potential calculator based on sequence intrinsic features. Nucleic Acids Res. 45(Web Server issue), W12\u2013W16 (2017).","journal-title":"Nucleic Acids Res."},{"key":"44195_CR29","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1016\/j.cell.2015.02.019","volume":"161","author":"BB Chu","year":"2015","unstructured":"Chu, B. B. et al. Cholesterol transport through lysosome-peroxisome membrane contacts. Cell. 161, 291\u2013306 (2015).","journal-title":"Cell."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-44195-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-44195-2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-44195-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,17]],"date-time":"2022-12-17T09:48:59Z","timestamp":1671270539000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-44195-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,5,22]]},"references-count":29,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2019,12]]}},"alternative-id":["44195"],"URL":"https:\/\/doi.org\/10.1038\/s41598-019-44195-2","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,5,22]]},"assertion":[{"value":"18 July 2018","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 January 2019","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 May 2019","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"7693"}}