{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T16:57:32Z","timestamp":1791305852779,"version":"4.3.1"},"reference-count":93,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T00:00:00Z","timestamp":1787788800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T00:00:00Z","timestamp":1787788800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J Intern Med"],"published-print":{"date-parts":[[2026,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Hypocholesterolemia is perceived as benign given its association with lower cardiovascular risk. However, genetic and epidemiological evidence indicates that persistently low levels of low\u2010density lipoprotein cholesterol (LDL\u2010C) and apolipoprotein B (ApoB) arise from distinct biological mechanisms with different hepatic implications. Hypocholesterolemia may reflect either impaired hepatic assembly and secretion of ApoB\u2010containing lipoproteins or enhanced peripheral clearance of circulating lipoproteins, with divergent outcomes. Genetic defects disrupting ApoB\u2010dependent lipoprotein secretion, notably variants in apolipoprotein B gene (\n                    <jats:italic>APOB<\/jats:italic>\n                    ) and microsomal triglyceride transfer protein gene (\n                    <jats:italic>MTTP<\/jats:italic>\n                    ), limit hepatic lipid export and promote intrahepatic triglyceride retention, predisposing to steatosis and progressive liver disease without metabolic risk factors. Hypocholesterolemia driven by increased lipoprotein clearance, as observed with loss\u2010of\u2010function variants in proprotein convertase subtilisin\/kexin type 9 (\n                    <jats:italic>PCSK9<\/jats:italic>\n                    ) or angiopoietin\u2010like protein 3 (\n                    <jats:italic>ANGPTL3<\/jats:italic>\n                    ), produces lifelong LDL\u2010C reduction that is cardioprotective without consistent evidence of adverse hepatic outcomes. Cohort and sequencing studies demonstrate an increased burden of liver disease in secretion\u2010driven hypocholesterolemia but not in clearance\u2010driven phenotypes. These findings indicate that clinical consequences are determined by the underlying biological mechanism rather than the degree of cholesterol lowering. After exclusion of secondary causes, genetic testing may be considered in people with metabolic dysfunction\u2010associated steatotic liver disease (MASLD) and hypocholesterolemia to clarify the mechanism, guide follow\u2010up, and enable family cascade screening. In impaired secretion phenotype forms, lifelong MASLD monitoring may be warranted, with timely consideration of therapy if liver disease progresses. In clearance\u2010mediated phenotypes, management should follow standard MASLD risk stratification and care, without additional surveillance related to the genetic defect.\n                  <\/jats:p>","DOI":"10.1111\/joim.70142","type":"journal-article","created":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T08:52:05Z","timestamp":1787820725000},"page":"572-589","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Hypocholesterolemia in liver and cardiovascular disease: Friend or foe?"],"prefix":"10.1111","volume":"300","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-0887-2265","authenticated-orcid":false,"given":"Valentina","family":"Flagiello","sequence":"first","affiliation":[{"name":"Operative Research Unit of Clinical Medicine and Hepatology Fondazione Policlinico Universitario Campus Bio\u2010Medico  Roma Italy"},{"name":"Centre for Reproduction, Metabolism and Molecular Medicine (CeRM), Department of Medicine (H7) Karolinska Institute  Huddinge Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6467-5280","authenticated-orcid":false,"given":"Emelie","family":"Barreby","sequence":"additional","affiliation":[{"name":"Centre for Reproduction, Metabolism and Molecular Medicine (CeRM), Department of Medicine (H7) Karolinska Institute  Huddinge Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1138-1967","authenticated-orcid":false,"given":"Umberto","family":"Vespasiani\u2010Gentilucci","sequence":"additional","affiliation":[{"name":"Operative Research Unit of Clinical Medicine and Hepatology Fondazione Policlinico Universitario Campus Bio\u2010Medico  Roma Italy"},{"name":"Research Unit of Hepatology, Department of Medicine and Surgery Universit\u00e0 Campus Bio\u2010Medico di Roma  Roma Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9168-4898","authenticated-orcid":false,"given":"Stefano","family":"Romeo","sequence":"additional","affiliation":[{"name":"Centre for Reproduction, Metabolism and Molecular Medicine (CeRM), Department of Medicine (H7) Karolinska Institute  Huddinge Sweden"},{"name":"Department of Molecular and Clinical Medicine University of Gothenburg  Gothenburg Sweden"},{"name":"Department of Experimental and Clinical Medicine University Magna Graecia of Catanzaro  Catanzaro Italy"},{"name":"Department of Endocrinology Karolinska University Hospital  Huddinge Sweden"},{"name":"Department of Cardiology Sahlgrenska University Hospital  Gothenburg Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,27]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehaf190"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1080\/17446651.2023.2204932"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/joim.13694"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/joim.13793"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/joim.12614"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacl.2022.08.009"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2024.01.030"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2020.11.040"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI201762"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2019.01.026"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.R300002-JLR200"},{"key":"e_1_2_12_13_1","first-page":"93","article-title":"Apolipoprotein B: from editosome to proteasome","volume":"55","author":"Chan L","year":"2000","journal-title":"Recent Prog Horm Res."},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1186\/1743-7075-7-35"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1097\/00041433-200104000-00008"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-019-0190-7"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2025.112224"},{"key":"e_1_2_12_18_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1008955"},{"key":"e_1_2_12_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-47737-w"},{"key":"e_1_2_12_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2901"},{"key":"e_1_2_12_21_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.90920.2008"},{"key":"e_1_2_12_22_1","doi-asserted-by":"publisher","DOI":"10.1111\/joim.12003"},{"key":"e_1_2_12_23_1","doi-asserted-by":"publisher","DOI":"10.1111\/joim.13017"},{"key":"e_1_2_12_24_1","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehab551"},{"key":"e_1_2_12_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.atherosclerosis.2009.12.027"},{"key":"e_1_2_12_26_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.00195.2021"},{"key":"e_1_2_12_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.atherosclerosis.2011.07.019"},{"key":"e_1_2_12_28_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10545-008-0863-4"},{"key":"e_1_2_12_29_1","doi-asserted-by":"publisher","DOI":"10.1097\/MOL.0000000000000680"},{"key":"e_1_2_12_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2019.05.023"},{"key":"e_1_2_12_31_1","doi-asserted-by":"publisher","DOI":"10.1097\/MOL.0b013e32833854c0"},{"key":"e_1_2_12_32_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1612790"},{"key":"e_1_2_12_33_1","first-page":"70","article-title":"Rare loss\u2010of\u2010function mutations in ANGPTL family members contribute to plasma triglyceride levels in humans","volume":"119","author":"Romeo S","year":"2009","journal-title":"J Clin Invest."},{"key":"e_1_2_12_34_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12944-018-0659-y"},{"key":"e_1_2_12_35_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M208539200"},{"key":"e_1_2_12_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.atherosclerosis.2018.06.881"},{"key":"e_1_2_12_37_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2796.2009.02167.x"},{"key":"e_1_2_12_38_1","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.125.322498"},{"key":"e_1_2_12_39_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10545-013-9665-4"},{"key":"e_1_2_12_40_1","volume-title":"GeneReviews\u00ae","author":"Burnett JR","year":"1993"},{"key":"e_1_2_12_41_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.257"},{"key":"e_1_2_12_42_1","doi-asserted-by":"publisher","DOI":"10.1111\/liv.15837"},{"key":"e_1_2_12_43_1","doi-asserted-by":"publisher","DOI":"10.1111\/joim.12719"},{"key":"e_1_2_12_44_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.30874"},{"key":"e_1_2_12_45_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCGEN.118.002376"},{"key":"e_1_2_12_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.athplu.2022.06.001"},{"key":"e_1_2_12_47_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.ATV.0000176191.64314.07"},{"key":"e_1_2_12_48_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamacardio.2022.5271"},{"key":"e_1_2_12_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0168-8278(00)80270-6"},{"key":"e_1_2_12_50_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2014.05.023"},{"key":"e_1_2_12_51_1","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.112.301101"},{"key":"e_1_2_12_52_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-39998-2"},{"key":"e_1_2_12_53_1","doi-asserted-by":"publisher","DOI":"10.4274\/jcrpe.galenos.2019.2019.0144"},{"key":"e_1_2_12_54_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhepr.2023.100764"},{"key":"e_1_2_12_55_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12881-015-0242-6"},{"key":"e_1_2_12_56_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0185396"},{"key":"e_1_2_12_57_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12944-017-0570-y"},{"key":"e_1_2_12_58_1","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.R200014-JLR200"},{"key":"e_1_2_12_59_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa054013"},{"key":"e_1_2_12_60_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1002926"},{"key":"e_1_2_12_61_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2012-1298"},{"key":"e_1_2_12_62_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-04103-z"},{"key":"e_1_2_12_63_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.123.065866"},{"key":"e_1_2_12_64_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCGENETICS.116.001632"},{"key":"e_1_2_12_65_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2019.03.517"},{"key":"e_1_2_12_66_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamacardio.2020.5341"},{"key":"e_1_2_12_67_1","doi-asserted-by":"publisher","DOI":"10.1111\/liv.14711"},{"key":"e_1_2_12_68_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12916-015-0358-8"},{"key":"e_1_2_12_69_1","doi-asserted-by":"publisher","DOI":"10.1155\/2023\/7362551"},{"key":"e_1_2_12_70_1","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.123.319789"},{"key":"e_1_2_12_71_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2004215"},{"key":"e_1_2_12_72_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.122.059266"},{"key":"e_1_2_12_73_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-023-02494-2"},{"key":"e_1_2_12_74_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2024.04.031"},{"key":"e_1_2_12_75_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2021.05.025"},{"key":"e_1_2_12_76_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2309000"},{"key":"e_1_2_12_77_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI23621"},{"key":"e_1_2_12_78_1","first-page":"84","article-title":"Alcohol and the liver: metabolism of alcohol and its role in hepatic and extrahepatic diseases","volume":"67","author":"Lieber CS","year":"2000","journal-title":"Mt Sinai J Med."},{"key":"e_1_2_12_79_1","doi-asserted-by":"publisher","DOI":"10.35946\/arcr.v38.2.01"},{"key":"e_1_2_12_80_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2028395"},{"key":"e_1_2_12_81_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2413258"},{"key":"e_1_2_12_82_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2401943"},{"key":"e_1_2_12_83_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2026.04.011"},{"key":"e_1_2_12_84_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2015.05.044"},{"key":"e_1_2_12_85_1","doi-asserted-by":"publisher","DOI":"10.5551\/jat.RV17056"},{"key":"e_1_2_12_86_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mam.2018.03.001"},{"key":"e_1_2_12_87_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.27289"},{"key":"e_1_2_12_88_1","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.107.160192"},{"key":"e_1_2_12_89_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2015.01.036"},{"key":"e_1_2_12_90_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2796.2010.02305.x"},{"key":"e_1_2_12_91_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2015.05.006"},{"key":"e_1_2_12_92_1","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.M002915"},{"key":"e_1_2_12_93_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11883-020-00869-1"},{"key":"e_1_2_12_94_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacl.2014.08.002"}],"container-title":["Journal of Internal Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/joim.70142","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/joim.70142","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/joim.70142","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T16:42:31Z","timestamp":1791304951000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/joim.70142"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,27]]},"references-count":93,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2026,11]]}},"alternative-id":["10.1111\/joim.70142"],"URL":"https:\/\/doi.org\/10.1111\/joim.70142","archive":["Portico"],"relation":{},"ISSN":["0954-6820","1365-2796"],"issn-type":[{"value":"0954-6820","type":"print"},{"value":"1365-2796","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,27]]},"assertion":[{"value":"2026-08-27","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}