{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,18]],"date-time":"2026-10-18T09:59:59Z","timestamp":1792317599445,"version":"4.4.0"},"reference-count":84,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2024,12,3]],"date-time":"2024-12-03T00:00:00Z","timestamp":1733184000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100007710","name":"University of Connecticut","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007710","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["pathsocjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Pathology"],"published-print":{"date-parts":[[2025,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    The pathogenesis of alcohol\u2010related liver disease (ALD) is closely linked to mitochondrial dysfunction and impaired cellular energy metabolism. In this study, we explored how ethanol triggers inflammation, oxidative stress, and mitochondrial dysfunction in Kupffer cells, i.e.hepatic resident macrophages, primarily focusing on the mitochondrial unfolded protein response (UPR\n                    <jats:sup>mt<\/jats:sup>\n                    ) using immortalized mouse Kupffer cells (ImKCs) and mouse primary KCs. The UPR\n                    <jats:sup>mt<\/jats:sup>\n                    is a cellular defense mechanism activated in response to the perturbation of mitochondrial proteostasis to maintain mitochondrial integrity and function by upregulating the expression of mitochondrial chaperones and proteases. We also determined whether nicotinamide riboside (NR), a NAD\n                    <jats:sup>+<\/jats:sup>\n                    precursor, could mitigate ethanol\u2010triggered cellular damage. When ImKCs were exposed to 80\u2009m\n                    <jats:sc>m<\/jats:sc>\n                    ethanol for 72\u2009h, they displayed inflammation, oxidative stress, and impaired mitochondrial function with decreased mitochondrial content and deformed mitochondrial crista structure. NR, however, counteracted the effects of ethanol. Furthermore, ethanol increased mRNA and protein levels of UPR\n                    <jats:sup>mt<\/jats:sup>\n                    genes, such as mitochondrial chaperones and proteases, which were attenuated by NR. Notably, the ethanol\u2010induced shift in the entry of activating transcription factor 5 (ATF5), a putative transcriptional regulator of UPR\n                    <jats:sup>mt<\/jats:sup>\n                    , to the nucleus from the mitochondria was abolished by NR. The induction of UPR\n                    <jats:sup>mt<\/jats:sup>\n                    genes by ethanol was significantly repressed when\n                    <jats:italic>Atf5<\/jats:italic>\n                    was knocked down, indicating the role of ATF5 in the induction of UPR\n                    <jats:sup>mt<\/jats:sup>\n                    genes in ImKCs exposed to ethanol. We also confirmed the induction of UPR\n                    <jats:sup>mt<\/jats:sup>\n                    gene expression in mouse and human livers exposed to alcohol. Our findings demonstrate the ability of NR to alleviate ethanol\u2010induced oxidative stress, inflammation, and mitochondrial dysfunction, partly by modulating the ATF5\u2010dependent UPR\n                    <jats:sup>mt<\/jats:sup>\n                    pathway in ImKCs, suggesting its potential for ALD therapy. \u00a9 2024 The Pathological Society of Great Britain and Ireland.\n                  <\/jats:p>","DOI":"10.1002\/path.6372","type":"journal-article","created":{"date-parts":[[2024,12,3]],"date-time":"2024-12-03T04:42:04Z","timestamp":1733200924000},"page":"110-122","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Nicotinamide riboside targets mitochondrial unfolded protein response to reduce alcohol\u2010induced damage in\n                    <scp>K<\/scp>\n                    upffer cells"],"prefix":"10.1002","volume":"265","author":[{"given":"Jaeeun","family":"Lee","sequence":"first","affiliation":[{"name":"Department of Nutritional Sciences University of Connecticut  Storrs CT USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hayoung","family":"Woo","sequence":"additional","affiliation":[{"name":"Department of Nutritional Sciences University of Connecticut  Storrs CT USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6061-2928","authenticated-orcid":false,"given":"Hyunju","family":"Kang","sequence":"additional","affiliation":[{"name":"Department of Nutritional Sciences University of Connecticut  Storrs CT USA"},{"name":"Department of Food and Nutrition Keimyung University  Daegu South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Young\u2010Ki","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Nutritional Sciences University of Connecticut  Storrs CT USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7945-793X","authenticated-orcid":false,"given":"Ji\u2010Young","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Nutritional Sciences University of Connecticut  Storrs CT USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,12,3]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2018.12.003"},{"key":"e_1_2_8_3_1","doi-asserted-by":"crossref","unstructured":"Spencer MR Curtin SC Garnett MF. Alcohol\u2010induced death rates in the United States 2019\u20132020. NCHS Data Brief no 448. Hyattsville MD: National Center for Health Statistics. 2022. [Accessed 22 November 2024]. Available from:https:\/\/www.cdc.gov\/nchs\/products\/databriefs\/db448.htm","DOI":"10.15620\/cdc:121795"},{"key":"e_1_2_8_4_1","unstructured":"ChenCM YoonY\u2010H.Surveillance report #118: liver cirrhosis mortality in the United States: national state and regional trends 2000\u20132019. NIAAA Division of Epidemiology and Prevention Research: Rockville MD 2022. [Accessed 22 November 2024]. Available from:https:\/\/www.niaaa.nih.gov\/publications\/surveillance-reports\/surveillance118"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41423-020-00579-3"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-nutr-072610-145138"},{"key":"e_1_2_8_7_1","doi-asserted-by":"crossref","first-page":"147","DOI":"10.35946\/arcr.v38.2.01","article-title":"Alcoholic liver disease: pathogenesis and current management","volume":"38","author":"Osna NA","year":"2017","journal-title":"Alcohol Res"},{"key":"e_1_2_8_8_1","doi-asserted-by":"crossref","first-page":"251","DOI":"10.35946\/arcr.v37.2.09","article-title":"Macrophages and alcohol\u2010related liver inflammation","volume":"37","author":"Ju C","year":"2015","journal-title":"Alcohol Res"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2016.00538"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v20.i47.17756"},{"key":"e_1_2_8_11_1","first-page":"113","article-title":"Current management of alcoholic hepatitis and future therapies","volume":"4","author":"Saberi B","year":"2016","journal-title":"J Clin Transl Hepatol"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.1840220441"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-020-00313-x"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-020-00311-7"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.21004"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cld.2012.08.002"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2018.04.006"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/fsn3.2007"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2018.06.083"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1080\/07853890510007368"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jnutbio.2020.108477"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbalip.2020.158838"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41374-021-00599-1"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/cdf445"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature12188"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2010.12.016"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.201903166R"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cyto.2014.07.251"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbagen.2014.10.014"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbagen.2013.01.018"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2019.06.009"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nutres.2007.11.008"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1089\/jmf.2016.0119"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jnutbio.2019.06.001"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.3390\/nu8060381"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2013.032"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cld.2012.03.015"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0168-8278(12)60005-1"},{"key":"e_1_2_8_39_1","first-page":"5","article-title":"The genetics of alcohol metabolism: role of alcohol dehydrogenase and aldehyde dehydrogenase variants","volume":"30","author":"Edenberg HJ","year":"2007","journal-title":"Alcohol Res Health"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature25154"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2017.7269"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmet.2021.101195"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2010.09.019"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2017.04.088"},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a033944"},{"key":"e_1_2_8_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2016.06.002"},{"key":"e_1_2_8_47_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2020.00515"},{"key":"e_1_2_8_48_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-021-03993-1"},{"key":"e_1_2_8_49_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.R117.791061"},{"key":"e_1_2_8_50_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13045-022-01317-0"},{"key":"e_1_2_8_51_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0891-5849(01)00748-1"},{"key":"e_1_2_8_52_1","doi-asserted-by":"publisher","DOI":"10.1155\/2014\/149185"},{"key":"e_1_2_8_53_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2007.05.005"},{"key":"e_1_2_8_54_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00018.2001"},{"key":"e_1_2_8_55_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep4.1115"},{"key":"e_1_2_8_56_1","doi-asserted-by":"publisher","DOI":"10.1124\/mol.111.071126"},{"key":"e_1_2_8_57_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41572-018-0014-7"},{"key":"e_1_2_8_58_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2019.09.001"},{"key":"e_1_2_8_59_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-021-00723-z"},{"key":"e_1_2_8_60_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0212523"},{"key":"e_1_2_8_61_1","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2014-0117OC"},{"key":"e_1_2_8_62_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-22923-5"},{"key":"e_1_2_8_63_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2017.04.098"},{"key":"e_1_2_8_64_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2023.110717"},{"key":"e_1_2_8_65_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2013.05.049"},{"key":"e_1_2_8_66_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2020.101650"},{"key":"e_1_2_8_67_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2017.04.020"},{"key":"e_1_2_8_68_1","doi-asserted-by":"publisher","DOI":"10.1093\/alcalc\/agl017"},{"key":"e_1_2_8_69_1","doi-asserted-by":"publisher","DOI":"10.1002\/j.2040-4603.2013.tb00510.x"},{"key":"e_1_2_8_70_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12915-015-0201-x"},{"key":"e_1_2_8_71_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.08.032"},{"key":"e_1_2_8_72_1","doi-asserted-by":"publisher","DOI":"10.1111\/acel.13419"},{"key":"e_1_2_8_73_1","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2022.0173"},{"key":"e_1_2_8_74_1","doi-asserted-by":"publisher","DOI":"10.1080\/15384101.2017.1285631"},{"key":"e_1_2_8_75_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2022.102037"},{"key":"e_1_2_8_76_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abi8886"},{"key":"e_1_2_8_77_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1432-1033.1996.0098h.x"},{"key":"e_1_2_8_78_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1223560"},{"key":"e_1_2_8_79_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature13818"},{"key":"e_1_2_8_80_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1294-17.2017"},{"key":"e_1_2_8_81_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2016.06.008"},{"key":"e_1_2_8_82_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature17989"},{"key":"e_1_2_8_83_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2017.07.007"},{"key":"e_1_2_8_84_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gendis.2021.04.008"},{"key":"e_1_2_8_85_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.addr.2017.05.007"}],"container-title":["The Journal of Pathology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pathsocjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/path.6372","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T18:09:07Z","timestamp":1761070147000},"score":1,"resource":{"primary":{"URL":"https:\/\/pathsocjournals.onlinelibrary.wiley.com\/doi\/10.1002\/path.6372"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,3]]},"references-count":84,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2025,1]]}},"alternative-id":["10.1002\/path.6372"],"URL":"https:\/\/doi.org\/10.1002\/path.6372","archive":["Portico"],"relation":{},"ISSN":["0022-3417","1096-9896"],"issn-type":[{"value":"0022-3417","type":"print"},{"value":"1096-9896","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,12,3]]},"assertion":[{"value":"2024-05-11","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-10-23","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-12-03","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}