{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,6]],"date-time":"2026-11-06T20:45:39Z","timestamp":1793997939991,"version":"4.8.0"},"reference-count":44,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2020,11,24]],"date-time":"2020-11-24T00:00:00Z","timestamp":1606176000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002848","name":"Comisi\u00f3n Nacional de Investigaci\u00f3n Cient\u00edfica y Tecnol\u00f3gica","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002848","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["faseb.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FASEB Journal"],"published-print":{"date-parts":[[2021,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Liver fibrosis is characterized by the accumulation of extracellular matrix proteins, mainly composed of collagen. Hepatic stellate cells (HSCs) mediate liver fibrosis by secreting collagen. Vitamin C (ascorbic acid) is a cofactor of prolyl\u2010hydroxylases that modify newly synthesized collagen on the route for secretion. Unlike most animals, humans cannot synthesize ascorbic acid and its role in liver fibrosis remains unclear. Here, we determined the effect of ascorbic acid and prolyl\u2010hydroxylase inhibition on collagen production and secretion by human HSCs. Primary human HSCs (p\u2010hHSCs) and the human HSCscell line LX\u20102 were treated with ascorbic acid, transforming growth factor\u2010beta (TGF\u03b2) and\/or the pan\u2010hydroxylase inhibitor dimethyloxalylglycine (DMOG). Expression of collagen\u2010I was analyzed by RT\u2010qPCR (\n                    <jats:italic>COL1A1<\/jats:italic>\n                    ), Western blotting, and immunofluorescence microscopy. Collagen secretion was determined in the medium by Western blotting for collagen\u2010I and by HPLC for hydroxyproline concentrations. Expression of solute carrier family 23 members 1 and 2 (\n                    <jats:italic>SLC23A1<\/jats:italic>\n                    \/\n                    <jats:italic>SLC23A<\/jats:italic>\n                    2), encoding sodium\u2010dependent vitamin C transporters 1 and 2 (SVCT1\/SVCT2) was quantified in healthy and cirrhotic human tissue. In the absence of ascorbic acid, collagen\u2010I accumulated intracellularly in p\u2010hHSCs and LX\u20102 cells, which was potentiated by TGF\u03b2. Ascorbic acid co\u2010treatment strongly promoted collagen\u2010I excretion and enhanced extracellular hydroxyproline concentrations, without affecting collagen\u2010I (\n                    <jats:italic>COL1A1<\/jats:italic>\n                    ) mRNA levels. DMOG inhibited collagen\u2010I release even in the presence of ascorbic acid and suppressed\n                    <jats:italic>COL1A1<\/jats:italic>\n                    and alpha\u2010smooth muscle actin (\u03b1SMA\/\n                    <jats:italic>ACTA2<\/jats:italic>\n                    ) mRNA levels, also under hypoxic conditions. Hepatocytes express both ascorbic acid transporters, while p\u2010hHSCs and LX\u20102 express the only SVCT2, which is selectively enhanced in cirrhotic livers. Human HSCs rely on ascorbic acid for the efficient secretion of collagen\u2010I, which can be effectively blocked by hydroxylase antagonists, revealing new therapeutic targets to treat liver fibrosis.\n                  <\/jats:p>","DOI":"10.1096\/fj.202001564rr","type":"journal-article","created":{"date-parts":[[2020,11,25]],"date-time":"2020-11-25T02:32:50Z","timestamp":1606271570000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["Collagen release by human hepatic stellate cells requires vitamin C and is efficiently blocked by hydroxylase inhibition"],"prefix":"10.1096","volume":"35","author":[{"given":"Natalia","family":"Smith\u2010Cortinez","sequence":"first","affiliation":[{"name":"Department of Hepatology and Gastroenterology University Medical Center Groningen University of Groningen  Groningen the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raphael R.","family":"Fagundes","sequence":"additional","affiliation":[{"name":"Department of Hepatology and Gastroenterology University Medical Center Groningen University of Groningen  Groningen the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Gomez","sequence":"additional","affiliation":[{"name":"Tytgat Institute for Liver and Intestinal Research Amsterdam Gastroenterology and Metabolism Amsterdam UMC University of Amsterdam  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Defu","family":"Kong","sequence":"additional","affiliation":[{"name":"Department of Hepatology and Gastroenterology University Medical Center Groningen University of Groningen  Groningen the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dirk R.","family":"de Waart","sequence":"additional","affiliation":[{"name":"Tytgat Institute for Liver and Intestinal Research Amsterdam Gastroenterology and Metabolism Amsterdam UMC University of Amsterdam  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janette","family":"Heegsma","sequence":"additional","affiliation":[{"name":"Department of Hepatology and Gastroenterology University Medical Center Groningen University of Groningen  Groningen the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Svenja","family":"Sydor","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine University Hospital Knappschaftskrankenhaus Ruhr\u2010University Bochum  Bochum Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Olinga","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Technology and Biopharmacy University of Groningen  Groningen the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent E.","family":"de Meijer","sequence":"additional","affiliation":[{"name":"Department of Surgery Division of Hepato\u2010Pancreato\u2010Biliary Surgery and Liver Transplantation University Medical Center Groningen University of Groningen  Groningen the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cormac T.","family":"Taylor","sequence":"additional","affiliation":[{"name":"School of Medicine and Medical Science and the Conway Institute University College Dublin  Dublin Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruud","family":"Bank","sequence":"additional","affiliation":[{"name":"Department of Pathology and Medical Biology University Medical Center Groningen University of Groningen  Groningen the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Coen C.","family":"Paulusma","sequence":"additional","affiliation":[{"name":"Tytgat Institute for Liver and Intestinal Research Amsterdam Gastroenterology and Metabolism Amsterdam UMC University of Amsterdam  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klaas Nico","family":"Faber","sequence":"additional","affiliation":[{"name":"Department of Hepatology and Gastroenterology University Medical Center Groningen University of Groningen  Groningen the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,11,24]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrgastro.2017.38"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.addr.2017.05.007"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI24282"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.3238\/arztebl.2013.0083"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbalip.2017.01.007"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.3390\/nu10010029"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2013.5697"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.biochem.6b00251"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1155\/2017\/8936156"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0945-053X(03)00006-4"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.21.14884"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1042\/bse0520113"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.14814\/phy2.13324"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1111\/odi.12446"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v16.i3.281"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(19)84800-7"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1179\/1351000212Y.0000000038"},{"key":"e_1_2_9_19_1","first-page":"2820","article-title":"Anticytoproliferative effect of Vitamin C on rat hepatic stellate cell","volume":"8","author":"Su M","year":"2016","journal-title":"Am J Transl Res"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.23499"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.1041380103"},{"key":"e_1_2_9_22_1","first-page":"43","article-title":"Evolution of chemosensory receptor genes in primates and other mammals","volume":"269","author":"Niimura Y","year":"2012","journal-title":"J Biol Chem"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/0003-9861(88)90093-8"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1136\/gut.2004.042127"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00726-007-0555-7"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0138655"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbalip.2019.05.012"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.21528"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0378-4347(00)84655-1"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20133278"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.421636"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0705680105"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.febslet.2006.12.010"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0151736"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.addr.2017.07.014"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells8070721"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.1994.1549"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0511225103"},{"key":"e_1_2_9_39_1","first-page":"91","article-title":"Determination of L\u2010ascorbic acid levels in culture medium: Concentrations in commercial media and maintenance of levels under conditions of organ culture","volume":"13","author":"Feng J","year":"1977","journal-title":"Vitr J Tissue Cult Assoc"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00394-013-0536-4"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1017\/S0007114511002273"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.510230416"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.1007\/s005350050277"},{"key":"e_1_2_9_44_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.510280217"},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.00229.2016"}],"container-title":["The FASEB Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1096\/fj.202001564RR","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1096\/fj.202001564RR","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/faseb.onlinelibrary.wiley.com\/doi\/pdf\/10.1096\/fj.202001564RR","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T23:33:26Z","timestamp":1761694406000},"score":1,"resource":{"primary":{"URL":"https:\/\/faseb.onlinelibrary.wiley.com\/doi\/10.1096\/fj.202001564RR"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,11,24]]},"references-count":44,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2021,2]]}},"alternative-id":["10.1096\/fj.202001564RR"],"URL":"https:\/\/doi.org\/10.1096\/fj.202001564rr","archive":["Portico"],"relation":{},"ISSN":["0892-6638","1530-6860"],"issn-type":[{"value":"0892-6638","type":"print"},{"value":"1530-6860","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,11,24]]},"assertion":[{"value":"2020-06-19","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-11-10","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-11-24","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e21219"}}