{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T18:52:11Z","timestamp":1790707931337,"version":"4.1.0"},"reference-count":43,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2016,11,15]],"date-time":"2016-11-15T00:00:00Z","timestamp":1479168000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2016,11,15]],"date-time":"2016-11-15T00:00:00Z","timestamp":1479168000000},"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>Emerging evidence implies a key role of angiopoietin-like protein 8 (<jats:italic>Angptl8<\/jats:italic>) in the metabolic transition between fasting and feeding, whereas much less is known about the mechanism of its own expression. Here we show that hepatic <jats:italic>Angptl8<\/jats:italic> is rhythmically expressed, which involving the liver X receptor alpha (LXR\u03b1) and glucocorticoid receptor (GR) modulation during feeding and fasting periods, respectively. In addition, <jats:italic>Angptl8<\/jats:italic> mRNA is very unstable, which contributes to the nature of its daily rhythmicity by rapidly responding to fasting\/feeding transition. To explore its pathological function in dexamethasone (DEX)-induced fatty liver, we reversed its suppression by glucocorticoids through adenoviral delivery of <jats:italic>Angptl8<\/jats:italic> gene in mouse liver. Surprisingly, hepatic overexpression of Angptl8 dramatically elevated plasma triglyceride (TG) and non-esterified fatty acid (NEFA) levels in DEX-treated mice, suggesting a metabolic interaction between Angptl8 and glucocorticoid signaling. Moreover, intracellular hepatic Angptl8 is implicated in the regulation of lipid homeostasis by the experiments with ectopic expression of a nonsecreted Angptl8 mutant (\u039425-Angptl8). Altogether, our data demonstrate the molecular mechanism of the diurnal rhythm of <jats:italic>Angptl8<\/jats:italic> expression regulated by glucocorticoid signaling and LXR\u03b1 pathway, and provide new evidence to understand the role of Angptl8 in maintaining plasma TG homeostasis.<\/jats:p>","DOI":"10.1038\/srep36926","type":"journal-article","created":{"date-parts":[[2016,11,15]],"date-time":"2016-11-15T11:18:08Z","timestamp":1479208688000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":53,"title":["Fasting and Feeding Signals Control the Oscillatory Expression of Angptl8 to Modulate Lipid Metabolism"],"prefix":"10.1038","volume":"6","author":[{"given":"Fabin","family":"Dang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rong","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pengfei","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuting","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Md. Shofiul","family":"Azam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaqiong","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2016,11,15]]},"reference":[{"key":"BFsrep36926_CR1","doi-asserted-by":"publisher","first-page":"47","DOI":"10.5551\/jat1994.2.Supplement1_S47","volume":"2","author":"Y Osono","year":"1995","unstructured":"Osono, Y., Nakajima, K. & Hata, Y. Hypertriglyceridemia and fatty liver: clinical diagnosis of fatty liver and lipoprotein profiles in hypertriglyceridemic patients with fatty liver. J. Atheroscler Thromb. 2, 47\u201352 (1995).","journal-title":"J. Atheroscler Thromb."},{"key":"BFsrep36926_CR2","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1016\/S0002-9149(99)00211-8","volume":"83","author":"SM Grundy","year":"1999","unstructured":"Grundy, S. M. Hypertriglyceridemia insulin resistance and the metabolic syndrome. Am J Cardiol. 83, 25\u201329 (1999).","journal-title":"Am J Cardiol"},{"key":"BFsrep36926_CR3","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1016\/S0021-9150(98)00212-3","volume":"141","author":"MJ Marleen","year":"1998","unstructured":"Marleen, M. J. et al. Chylomicron synthesis by intestinal cells in vitro and in vivo. Atherosclerosis. 141, 9\u201316 (1998).","journal-title":"Atherosclerosis"},{"key":"BFsrep36926_CR4","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1042\/bst0320059","volume":"32","author":"GF Gibbons","year":"2004","unstructured":"Gibbons, G. F. et al. Synthesis and function of hepatic very-low-density lipoprotein. Biochem Soc Trans. 32, 59\u201364 (2004).","journal-title":"Biochem Soc Trans"},{"key":"BFsrep36926_CR5","doi-asserted-by":"publisher","first-page":"385","DOI":"10.2217\/17460875.3.4.385","volume":"3","author":"R Franssen","year":"2008","unstructured":"Franssen, R. et al. Role of lipoprotein lipase in triglyceride metabolism: potential therapeautic target. Future lipidol. 3, 385\u2013397 (2008).","journal-title":"Future lipidol"},{"key":"BFsrep36926_CR6","doi-asserted-by":"publisher","first-page":"473","DOI":"10.1016\/j.molmed.2005.08.002","volume":"11","author":"Y Oike","year":"2005","unstructured":"Oike, Y., Akao, M., Kubota, Y. & Suda, T. Angiopoietin-like proteins: potential new targets for metabolic syndrome therapy. Trends Mol Med. 11, 473\u2013479 (2005).","journal-title":"Trends Mol Med"},{"key":"BFsrep36926_CR7","doi-asserted-by":"publisher","first-page":"782","DOI":"10.1016\/j.bbalip.2011.10.010","volume":"1821","author":"F Mattijssen","year":"2012","unstructured":"Mattijssen, F. & Kersten, S. Regulation of triglyceride metabolism by Angiopoietin-like proteins. Biochim Biophys Acta. 1821, 782\u2013789 (2012).","journal-title":"Biochim Biophys Acta"},{"key":"BFsrep36926_CR8","doi-asserted-by":"publisher","first-page":"21344","DOI":"10.1074\/jbc.M213202200","volume":"278","author":"T Inaba","year":"2003","unstructured":"Inaba, T. et al. Angiopoietin-like protein 3 mediates hypertriglyceridemia induced by Liver X receptor. J. Biol Chem. 278, 21344\u201321351 (2003).","journal-title":"J. Biol Chem."},{"key":"BFsrep36926_CR9","doi-asserted-by":"publisher","first-page":"4943","DOI":"10.1210\/en.2005-0476","volume":"146","author":"A Koster","year":"2005","unstructured":"Koster, A. et al. Transgenic angiopoietin-like (angptl)4 overexpression and targeted disruption of angptl4 and angptl3: regulation of triglyceride metabolism. Endocrinology. 146, 4943\u20134950 (2005).","journal-title":"Endocrinology"},{"key":"BFsrep36926_CR10","doi-asserted-by":"publisher","first-page":"28524","DOI":"10.1074\/jbc.M113.497602","volume":"288","author":"MJ Lafferty","year":"2013","unstructured":"Lafferty, M. J. et al. Angiopoietin-like protein 4 inhibition of lipoprotein lipase: evidence for reversible complex formation. J Biol Chem. 288, 28524\u201328534 (2013).","journal-title":"J Biol Chem"},{"key":"BFsrep36926_CR11","doi-asserted-by":"publisher","first-page":"19751","DOI":"10.1073\/pnas.1217552109","volume":"109","author":"F Quagliarini","year":"2012","unstructured":"Quagliarini, F. et al. Atypical angiopoietin-like protein that regulates ANGPTL3. Proc Natl Acad Sci USA. 109, 19751\u201319756 (2012).","journal-title":"Proc Natl Acad Sci USA"},{"key":"BFsrep36926_CR12","doi-asserted-by":"publisher","first-page":"1126","DOI":"10.1016\/j.bbrc.2012.12.025","volume":"430","author":"Z Fu","year":"2013","unstructured":"Fu, Z. et al. Lipasin, thermoregulated in brown fat, is a novel but atypical member of the angiopoietin-like protein family. Biochem Biophys Res Commun. 430, 1126\u20131131 (2013).","journal-title":"Biochem Biophys Res Commun"},{"key":"BFsrep36926_CR13","doi-asserted-by":"publisher","first-page":"16109","DOI":"10.1073\/pnas.1315292110","volume":"110","author":"Y Wang","year":"2013","unstructured":"Wang, Y. et al. Mice lacking ANGPTL8 (Betatrophin) manifest disrupted triglyceride metabolism without impaired glucose homeostasis. Proc Natl Acad Sci USA. 110, 16109\u201316114 (2013).","journal-title":"Proc Natl Acad Sci USA"},{"key":"BFsrep36926_CR14","doi-asserted-by":"publisher","first-page":"28488","DOI":"10.1074\/jbc.M004029200","volume":"275","author":"S Kersten","year":"2000","unstructured":"Kersten, S. et al. Characterization of the fasting-induced adipose factor FIAF, a novel peroxisome proliferator-activated receptor target gene. J. Biol Chem. 275, 28488\u201328493 (2000).","journal-title":"J. Biol Chem"},{"key":"BFsrep36926_CR15","doi-asserted-by":"publisher","first-page":"E334","DOI":"10.1152\/ajpendo.00084.2012","volume":"303","author":"G Ren","year":"2012","unstructured":"Ren, G., Kim, J. Y. & Smas, C. M. Identification of RIFL, a novel adipocyte-enriched insulin target gene with a role in lipid metabolism. Am J Physiol Endocrinol Metab. 303, E334\u2013E351 (2012).","journal-title":"Am J Physiol Endocrinol Metab"},{"key":"BFsrep36926_CR16","doi-asserted-by":"publisher","first-page":"786","DOI":"10.1016\/j.bbrc.2012.07.038","volume":"424","author":"Z Ren","year":"2012","unstructured":"Ren, Z. Lipasin, a novel nutritionally-regulated liver-enriched factor that regulates serum triglyceride levels. Biochem Biophys Res Commun. 424, 786\u2013792 (2012).","journal-title":"Biochem Biophys Res Commun"},{"key":"BFsrep36926_CR17","doi-asserted-by":"publisher","first-page":"148","DOI":"10.1016\/j.mce.2015.07.031","volume":"414","author":"J Lee","year":"2015","unstructured":"Lee, J. et al. AMP-activated protein kinase suppresses the expression of LXR\/SREBP-1 signaling-induced ANGPTL8 in HepG2 cells. Mol Cell Endocrinol. 414, 148\u2013155 (2015).","journal-title":"Mol Cell Endocrinol"},{"key":"BFsrep36926_CR18","doi-asserted-by":"publisher","first-page":"45","DOI":"10.14345\/ceth.14013","volume":"1","author":"K Nakajima","year":"2014","unstructured":"Nakajima, K. Remnant Lipoproteins: A Subfraction of Plasma Triglyceride-Rich Lipoproteins Associated with Postprandial Hyperlipidemia. Clinical & Experimental Thrombosis and Hemostasis. 1, 45\u201353 (2014).","journal-title":"Clinical & Experimental Thrombosis and Hemostasis"},{"key":"BFsrep36926_CR19","doi-asserted-by":"publisher","first-page":"691","DOI":"10.1016\/j.cell.2014.09.027","volume":"159","author":"V Gusarova","year":"2014","unstructured":"Gusarova, V. et al. ANGPTL8\/Betatrophin Does Not Control Pancreatic Beta Cell Expansion. Cell. 159, 691\u2013696 (2014).","journal-title":"Cell"},{"key":"BFsrep36926_CR20","doi-asserted-by":"publisher","first-page":"348","DOI":"10.1038\/nature11704","volume":"491","author":"J Bass","year":"2012","unstructured":"Bass, J. Circadian topology of metabolism. Nature. 491, 348\u2013356 (2012).","journal-title":"Nature"},{"key":"BFsrep36926_CR21","doi-asserted-by":"publisher","first-page":"e25231","DOI":"10.1371\/journal.pone.0025231","volume":"6","author":"S Shimba","year":"2011","unstructured":"Shimba, S. et al. Deficient of a clock gene, brain and muscle arnt-like protein-1 (BMAL1), induces dyslipidemia and ectopic fat formation. PLoS One. 6, e25231 (2011).","journal-title":"PLoS One"},{"key":"BFsrep36926_CR22","doi-asserted-by":"publisher","first-page":"2189","DOI":"10.1074\/jbc.M114.612358","volume":"290","author":"X Sun","year":"2015","unstructured":"Sun, X. et al. Glucagon-CREB\/CRTC2 signaling cascade regulates hepatic BMAL1 protein. J. Biol Chem. 290, 2189\u20132197 (2015).","journal-title":"J. Biol Chem."},{"key":"BFsrep36926_CR23","doi-asserted-by":"publisher","first-page":"3799","DOI":"10.1210\/endo.141.10.7708","volume":"141","author":"IP Torra","year":"2000","unstructured":"Torra, I. P. et al. Circadian and glucocorticoid regulation of rev-erba expression in liver. Endocrinology. 141, 3799\u20133806 (2000).","journal-title":"Endocrinology"},{"key":"BFsrep36926_CR24","doi-asserted-by":"publisher","first-page":"2108","DOI":"10.1101\/gad.5.11.2108","volume":"5","author":"DR Gallie","year":"1991","unstructured":"Gallie, D. R. The cap and polyA tail function synergistically to regulate mRNA translational efficiency. Genes Dev. 5, 2108\u20132116 (1991).","journal-title":"Genes Dev"},{"key":"BFsrep36926_CR25","doi-asserted-by":"publisher","first-page":"2005","DOI":"10.1182\/blood.V78.8.2005.2005","volume":"78","author":"M Akashi","year":"2005","unstructured":"Akashi, M. et al. Role of AUUU sequences in stabilization of granulocyte-macrophage colony stimulating factor RNA in stimulated cells. Blood. 78, 2005\u20132012 (2005).","journal-title":"Blood"},{"key":"BFsrep36926_CR26","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1016\/j.mce.2007.05.015","volume":"275","author":"A Vegiopoulos","year":"2007","unstructured":"Vegiopoulos, A. & Herzig, S. Glucocorticoids, metabolism and metabolic diseases. Mol Cell Endocrino. 275, 43\u201361 (2007).","journal-title":"Mol Cell Endocrino"},{"key":"BFsrep36926_CR27","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1016\/j.jsbmb.2015.07.020","volume":"154","author":"CP Woods","year":"2015","unstructured":"Woods, C. P., Hazlehurst, J. M. & Tomlinson, J. W. Glucocorticoids and non-alcoholic fatty liver disease. J Steroid Biochem Mol Biol. 154, 94\u2013103 (2015).","journal-title":"J Steroid Biochem Mol Biol"},{"key":"BFsrep36926_CR28","doi-asserted-by":"publisher","first-page":"935","DOI":"10.1038\/nature00965","volume":"418","author":"MR Steven","year":"2002","unstructured":"Steven, M. R. & David, R. W. Coordination of circadian timing in mammals. Nature. 418, 935\u2013941 (2002).","journal-title":"Nature"},{"key":"BFsrep36926_CR29","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1677\/JOE-08-0415","volume":"200","author":"T Dickmeis","year":"2009","unstructured":"Dickmeis, T. Glucocorticoids and the circadian clock. J. Endocrinol. 200, 3\u201322 (2009).","journal-title":"J. Endocrinol."},{"key":"BFsrep36926_CR30","doi-asserted-by":"publisher","first-page":"1138","DOI":"10.1016\/j.cell.2015.04.002","volume":"161","author":"JO Lipton","year":"2015","unstructured":"Lipton, J. O. et al. The Circadian Protein BMAL1 Regulates Translation in Response to S6K1-Mediated Phosphorylation. Cell. 161, 1138\u20131151 (2015).","journal-title":"Cell"},{"key":"BFsrep36926_CR31","doi-asserted-by":"publisher","first-page":"743","DOI":"10.1074\/jbc.M605023200","volume":"282","author":"JY Cha","year":"2007","unstructured":"Cha, J. Y. & Repa, J. J. The liver X receptor (LXR) and hepatic lipogenesis. The carbohydrate-response element-binding protein is a target gene of LXR. J. Biol Chem. 282, 743\u2013751 (2007).","journal-title":"J. Biol Chem."},{"key":"BFsrep36926_CR32","doi-asserted-by":"publisher","first-page":"136","DOI":"10.1194\/jlr.M200367-JLR200","volume":"44","author":"R Kaplan","year":"2002","unstructured":"Kaplan, R. et al. Regulation of the angiopoietin-like protein 3 gene by LXR. J. Lipid Res. 44, 136\u2013143 (2002).","journal-title":"J. Lipid Res"},{"key":"BFsrep36926_CR33","doi-asserted-by":"publisher","first-page":"1484","DOI":"10.1194\/jlr.M500005-JLR200","volume":"46","author":"H Ge","year":"2005","unstructured":"Ge, H. et al. Differential regulation and properties of angiopoietin-like proteins 3 and 4. J. Lipid Res. 46, 1484\u20131490 (2005).","journal-title":"J. Lipid Res."},{"key":"BFsrep36926_CR34","doi-asserted-by":"publisher","first-page":"25593","DOI":"10.1074\/jbc.M109.025452","volume":"284","author":"SK Koliwad","year":"2009","unstructured":"Koliwad, S. K. et al. Angiopoietin-like 4 (ANGPTL4, fasting-induced adipose factor) is a direct glucocorticoid receptor target and participates in glucocorticoid-regulated triglyceride metabolism. J. Biol Chem. 284, 25593\u201325601 (2009).","journal-title":"J. Biol Chem."},{"key":"BFsrep36926_CR35","doi-asserted-by":"publisher","first-page":"18502","DOI":"10.1038\/srep18502","volume":"5","author":"Z Fu","year":"2015","unstructured":"Fu, Z., Abou-Samra, A. B. & Zhang, R. A lipasin\/Angptl8 monoclonal antibody lowers mouse serum triglycerides involving increased postprandial activity of the cardiac lipoprotein lipase. Sci Rep. 5, 18502, doi: 10.1038\/srep18502 (2015).","journal-title":"Sci Rep."},{"key":"BFsrep36926_CR36","doi-asserted-by":"publisher","first-page":"e08428","DOI":"10.7554\/eLife.08428","volume":"4","author":"W Dijk","year":"2015","unstructured":"Dijk, W. et al. ANGPTL4 mediates shuttling of lipid fule to brown adipose tissue during sustained cold exposure. eLife. 4, e08428, doi: 10.7554\/eLife.08428 (2015).","journal-title":"eLife"},{"key":"BFsrep36926_CR37","doi-asserted-by":"publisher","first-page":"8444","DOI":"10.1074\/jbc.M111.294124","volume":"287","author":"NE Gray","year":"2012","unstructured":"Gray, N. E. et al. Angiopoietin-like 4 (Angptl4) protein is a physiological mediator of intracellular lipolysis in murine adipocytes. J. Biol Chem. 287, 8444\u20138456 (2012).","journal-title":"J. Biol Chem."},{"key":"BFsrep36926_CR38","doi-asserted-by":"publisher","first-page":"150272","DOI":"10.1098\/rsob.150272","volume":"6","author":"Zhang Ren","year":"2016","unstructured":"Ren, Zhang . The ANGPTL3-4-8 model, a molecular mechanism for triglyceride trafficking. Open Biol. 6, 150272, doi: 10.1098\/rsob.150272 (2016).","journal-title":"Open Biol."},{"key":"BFsrep36926_CR39","doi-asserted-by":"publisher","first-page":"819","DOI":"10.1126\/science.1231143","volume":"339","author":"L Cong","year":"2013","unstructured":"Cong, L. et al. Multiplex Genome Engineering Using CRISPR\/Cas Systems. Science. 339, 819\u2013823 (2013).","journal-title":"Science"},{"key":"BFsrep36926_CR40","doi-asserted-by":"publisher","first-page":"1236","DOI":"10.1038\/nprot.2007.135","volume":"2","author":"J Luo","year":"2007","unstructured":"Luo, J. et al. A protocol for rapid generation of recombinant adenoviruses using the AdEasy system. Nat Protoc. 2, 1236\u20131247 (2007).","journal-title":"Nat Protoc"},{"key":"BFsrep36926_CR41","doi-asserted-by":"publisher","first-page":"1101","DOI":"10.1038\/nprot.2008.73","volume":"3","author":"TD Schmittgen","year":"2008","unstructured":"Schmittgen, T. D. & Livak, K. J. Analyzing real-time PCR data by the comparative CT method. Nat Protoc. 3, 1101\u20131108 (2008).","journal-title":"Nat Protoc"},{"key":"BFsrep36926_CR42","doi-asserted-by":"publisher","first-page":"431","DOI":"10.1172\/JCI41681","volume":"121","author":"R Patel","year":"2011","unstructured":"Patel, R. et al. LXR\u03b2 is required for glucocorticoid-induced hyperglycemia and hepatosteatosis in mice. J. Clin Invest. 121, 431\u2013441 (2011).","journal-title":"J. Clin Invest."},{"key":"BFsrep36926_CR43","doi-asserted-by":"publisher","first-page":"2656","DOI":"10.1038\/ncomms3656","volume":"4","author":"Y Gao","year":"2013","unstructured":"Gao, Y. et al. Early adipogenesis is regulated through USP7-mediated deubiquitination of the histone acetyltransferase TIP60. Nat. Commun. 4, 2656, doi: 10.1038\/ncomms3656 (2013).","journal-title":"Nat. Commun."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/srep36926.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep36926","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep36926.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,5]],"date-time":"2023-01-05T02:41:41Z","timestamp":1672886501000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/srep36926"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,11,15]]},"references-count":43,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2016,12,23]]}},"alternative-id":["BFsrep36926"],"URL":"https:\/\/doi.org\/10.1038\/srep36926","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,11,15]]},"assertion":[{"value":"10 August 2016","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 October 2016","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 November 2016","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing financial interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"36926"}}