{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T22:58:50Z","timestamp":1791932330192,"version":"4.3.4"},"reference-count":72,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2024,2,2]],"date-time":"2024-02-02T00:00:00Z","timestamp":1706832000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,2,2]],"date-time":"2024-02-02T00:00:00Z","timestamp":1706832000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100012774","name":"Innovationsfonden","doi-asserted-by":"publisher","award":["1044-00127B"],"award-info":[{"award-number":["1044-00127B"]}],"id":[{"id":"10.13039\/100012774","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Gastroenterol"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Hepatocellular senescence may be a causal factor in the development and progression of non-alcoholic steatohepatitis (NASH). The most effective currently available treatment for NASH is lifestyle intervention, including dietary modification. This study aimed to evaluate the effects of dietary intervention on hallmarks of NASH and molecular signatures of hepatocellular senescence in the Gubra-Amylin NASH (GAN) diet-induced obese (DIO) and biopsy-confirmed mouse model of NASH.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>GAN DIO-NASH mice with liver biopsy-confirmed NASH and fibrosis received dietary intervention by switching to chow feeding (chow reversal) for 8, 16 or 24 weeks. Untreated GAN DIO-NASH mice and chow-fed C57BL\/6J mice served as controls. Pre-to-post liver biopsy histology was performed for within-subject evaluation of NAFLD Activity Score and fibrosis stage. Terminal endpoints included blood\/liver biochemistry, quantitative liver histology, mitochondrial respiration and RNA sequencing.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Chow-reversal promoted substantial benefits on metabolic outcomes and liver histology, as demonstrated by robust weight loss, complete resolution of hepatomegaly, hypercholesterolemia, elevated transaminase levels and hepatic steatosis in addition to attenuation of inflammatory markers. Notably, all DIO-NASH mice demonstrated\u2009\u2265\u20092 point significant improvement in NAFLD Activity Score following dietary intervention. While not improving fibrosis stage, chow-reversal reduced quantitative fibrosis markers (PSR, collagen 1a1, \u03b1-SMA), concurrent with improved liver mitochondrial respiration, complete reversal of p21 overexpression, lowered \u03b3-H2AX levels and widespread suppression of gene expression markers of hepatocellular senescence.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Dietary intervention (chow reversal) substantially improves metabolic, biochemical and histological hallmarks of NASH and fibrosis in GAN DIO-NASH mice. These benefits were reflected by progressive clearance of senescent hepatocellular cells, making the model suitable for profiling potential senotherapeutics in preclinical drug discovery for NASH.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12876-024-03141-x","type":"journal-article","created":{"date-parts":[[2024,2,2]],"date-time":"2024-02-02T00:14:59Z","timestamp":1706832899000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Dietary intervention reverses molecular markers of hepatocellular senescence in the GAN diet-induced obese and biopsy-confirmed mouse model of NASH"],"prefix":"10.1186","volume":"24","author":[{"given":"Mathias","family":"Flensted-Jensen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denise","family":"Or\u00f3","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma A.","family":"R\u00f8rbeck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin R\u00f8nn","family":"Madsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas Nygaard","family":"Madsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jenny","family":"Norlin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Feigh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steen","family":"Larsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henrik H.","family":"Hansen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,2,2]]},"reference":[{"key":"3141_CR1","doi-asserted-by":"publisher","unstructured":"Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global Epidemiology of Nonalcoholic Fatty Liver Disease-Meta-Analytic Assessment of Prevalence, Incidence, and Outcomes. 2015. https:\/\/doi.org\/10.1002\/hep.28431\/suppinfo.","DOI":"10.1002\/hep.28431\/suppinfo"},{"key":"3141_CR2","doi-asserted-by":"publisher","first-page":"1080","DOI":"10.1016\/j.metabol.2015.11.008","volume":"65","author":"GT Brown","year":"2016","unstructured":"Brown GT, Kleiner DE. Histopathology of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Metab Clin Exp. 2016;65:1080\u20136.","journal-title":"Metab Clin Exp"},{"key":"3141_CR3","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1038\/nrgastro.2016.147","volume":"14","author":"H Tilg","year":"2017","unstructured":"Tilg H, Moschen AR, Roden M. NAFLD and diabetes mellitus. Nat Rev Gastroenterol Hepatol. 2017;14:32\u201342.","journal-title":"Nat Rev Gastroenterol Hepatol"},{"key":"3141_CR4","doi-asserted-by":"publisher","unstructured":"Ratziu V, Giral P, Charlotte F, Bruckert E, Thibault V, Theodorou I, et al. Liver, pancreas, and biliary tract Liver Fibrosis in Overweight Patients. https:\/\/doi.org\/10.1053\/gast.2000.7964.","DOI":"10.1053\/gast.2000.7964"},{"key":"3141_CR5","doi-asserted-by":"publisher","first-page":"107843","DOI":"10.1016\/j.diabres.2019.107843","volume":"157","author":"P Saeedi","year":"2019","unstructured":"Saeedi P, Petersohn I, Salpea P, Malanda B, Karuranga S, Unwin N, et al. Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: results from the international diabetes federation diabetes atlas. Diabetes Res Clin Pract. 2019;157:107843.","journal-title":"Diabetes Res Clin Pract"},{"key":"3141_CR6","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1111\/liv.13301","volume":"37","author":"P Bedossa","year":"2017","unstructured":"Bedossa P. Pathology of non-alcoholic fatty liver disease. Liver Int. 2017;37:85\u20139.","journal-title":"Liver Int"},{"key":"3141_CR7","doi-asserted-by":"publisher","first-page":"389","DOI":"10.1053\/j.gastro.2015.04.043","volume":"149","author":"P Angulo","year":"2015","unstructured":"Angulo P, Kleiner DE, Dam-Larsen S, Adams LA, Bjornsson ES, Charatcharoenwitthaya P, et al. Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology. 2015;149:389-397.e10.","journal-title":"Gastroenterology"},{"key":"3141_CR8","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhepr.2021.100301","volume-title":"Evaluating causality of cellular senescence in non-alcoholic fatty liver disease","author":"AS Meijnikman","year":"2021","unstructured":"Meijnikman AS, Herrema H, Pascal T, Scheithauer M, Kroon J, Nieuwdorp M, et al. Evaluating causality of cellular senescence in non-alcoholic fatty liver disease. 2021."},{"key":"3141_CR9","doi-asserted-by":"publisher","first-page":"363","DOI":"10.1002\/hep.30834","volume":"71","author":"AM Papatheodoridi","year":"2020","unstructured":"Papatheodoridi AM, Chrysavgis L, Koutsilieris M, Chatzigeorgiou A. The role of senescence in the development of nonalcoholic fatty liver disease and progression to nonalcoholic steatohepatitis. Hepatology. 2020;71:363\u201374.","journal-title":"Hepatology"},{"key":"3141_CR10","doi-asserted-by":"publisher","first-page":"e12841","DOI":"10.1111\/acel.12841","volume":"18","author":"M Ogrodnik","year":"2019","unstructured":"Ogrodnik M, Salmonowicz H, Gladyshev VN. Integrating cellular senescence with the concept of damage accumulation in aging: relevance for clearance of senescent cells. Aging Cell. 2019;18:e12841.","journal-title":"Aging Cell"},{"key":"3141_CR11","doi-asserted-by":"publisher","first-page":"263","DOI":"10.1038\/s41574-020-0335-y","volume":"16","author":"S Khosla","year":"2020","unstructured":"Khosla S, Farr JN, Tchkonia T, Kirkland JL. The role of cellular senescence in ageing and endocrine disease. Nat Rev Endocrinol. 2020;16:263\u201375.","journal-title":"Nat Rev Endocrinol"},{"key":"3141_CR12","doi-asserted-by":"publisher","first-page":"729","DOI":"10.1038\/nrm2233","volume":"8","author":"J Campisi","year":"2007","unstructured":"Campisi J, D\u2019Adda Di Fagagna F. Cellular senescence: when bad things happen to good cells. Nat Rev Mol Cell Biol. 2007;8:729\u201340.","journal-title":"Nat Rev Mol Cell Biol"},{"key":"3141_CR13","doi-asserted-by":"publisher","first-page":"2221","DOI":"10.3390\/cells11142221","volume":"11","author":"P Wijayasiri","year":"2022","unstructured":"Wijayasiri P, Astbury S, Kaye P, Oakley F, Alexander GJ, Kendall TJ, et al. Role of hepatocyte senescence in the activation of hepatic stellate cells and liver fibrosis progression. Cells. 2022;11:2221.","journal-title":"Cells"},{"key":"3141_CR14","doi-asserted-by":"publisher","first-page":"15691","DOI":"10.1038\/ncomms15691","volume":"8","author":"M Ogrodnik","year":"2017","unstructured":"Ogrodnik M, Miwa S, Tchkonia T, Tiniakos D, Wilson CL, Lahat A, et al. Cellular senescence drives age-dependent hepatic steatosis. Nat Commun. 2017;8:15691.","journal-title":"Nat Commun"},{"key":"3141_CR15","doi-asserted-by":"publisher","first-page":"1489","DOI":"10.4161\/cc.28471","volume":"13","author":"A Aravinthan","year":"2014","unstructured":"Aravinthan A, Mells G, Allison M, Leathart J, Kotronen A, Yki-Jarvinen H, et al. Gene polymorphisms of cellular senescence marker p21 and disease progression in non-alcohol-related fatty liver disease. Cell Cycle. 2014;13:1489\u201394.","journal-title":"Cell Cycle"},{"key":"3141_CR16","doi-asserted-by":"publisher","first-page":"1007","DOI":"10.1038\/s42255-022-00620-x","volume":"4","author":"RK Baboota","year":"2022","unstructured":"Baboota RK, Rawshani A, Bonnet L, Li X, Yang H, Mardinoglu A, et al. BMP4 and Gremlin 1 regulate hepatic cell senescence during clinical progression of NAFLD\/NASH. Nat Metab. 2022;4:1007\u201321.","journal-title":"Nat Metab"},{"key":"3141_CR17","doi-asserted-by":"publisher","first-page":"957616","DOI":"10.3389\/fendo.2022.957616","volume":"13","author":"L Bonnet","year":"2022","unstructured":"Bonnet L, Alexandersson I, Baboota RK, Kroon T, Oscarsson J, Smith U, et al. Cellular senescence in hepatocytes contributes to metabolic disturbances in NASH. Front Endocrinol (Lausanne). 2022;13:957616.","journal-title":"Front Endocrinol (Lausanne)."},{"key":"3141_CR18","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1146\/annurev-genet-102108-134850","volume":"43","author":"C Wang","year":"2009","unstructured":"Wang C, Youle RJ. The role of mitochondria in apoptosis. Annu Rev Genet. 2009;43:95\u2013118.","journal-title":"Annu Rev Genet"},{"key":"3141_CR19","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3390\/antiox10030415","volume":"10","author":"P Hernansanz-Agust\u00edn","year":"2021","unstructured":"Hernansanz-Agust\u00edn P, Enr\u00edquez JA. Generation of reactive oxygen species by mitochondria. Antioxidants. 2021;10:1\u201318.","journal-title":"Antioxidants"},{"key":"3141_CR20","doi-asserted-by":"publisher","first-page":"e158447","DOI":"10.1172\/JCI158447","volume":"132","author":"S Miwa","year":"2022","unstructured":"Miwa S, Kashyap S, Chini E, von Zglinicki T. Mitochondrial dysfunction in cell senescence and aging. J Clin Invest. 2022;132:e158447.","journal-title":"J Clin Invest"},{"key":"3141_CR21","doi-asserted-by":"publisher","first-page":"701","DOI":"10.15252\/embj.201694025","volume":"35","author":"N Herranz","year":"2016","unstructured":"Herranz N, Gil J. Mitochondria and senescence: new actors for an old play. EMBO J. 2016;35:701\u20132.","journal-title":"EMBO J"},{"key":"3141_CR22","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1016\/j.ebiom.2017.03.020","volume":"21","author":"VI Korolchuk","year":"2017","unstructured":"Korolchuk VI, Miwa S, Carroll B, von Zglinicki T. Mitochondria in cell senescence: is mitophagy the weakest link? EBioMedicine. 2017;21:7\u201313.","journal-title":"EBioMedicine"},{"key":"3141_CR23","doi-asserted-by":"publisher","first-page":"112041","DOI":"10.1016\/j.biopha.2021.112041","volume":"142","author":"SA Dabravolski","year":"2021","unstructured":"Dabravolski SA, Bezsonov EE, Orekhov AN. The role of mitochondria dysfunction and hepatic senescence in NAFLD development and progression. Biomed Pharmacother. 2021;142:112041.","journal-title":"Biomed Pharmacother"},{"key":"3141_CR24","doi-asserted-by":"publisher","first-page":"829","DOI":"10.1016\/j.jhep.2017.05.016","volume":"67","author":"M Romero-G\u00f3mez","year":"2017","unstructured":"Romero-G\u00f3mez M, Zelber-Sagi S, Trenell M. Treatment of NAFLD with diet, physical activity and exercise. J Hepatol. 2017;67:829\u201346.","journal-title":"J Hepatol"},{"key":"3141_CR25","doi-asserted-by":"publisher","first-page":"908","DOI":"10.1038\/s41591-018-0104-9","volume":"24","author":"SL Friedman","year":"2018","unstructured":"Friedman SL, Neuschwander-Tetri BA, Rinella M, Sanyal AJ. Mechanisms of NAFLD development and therapeutic strategies. Nat Med. 2018;24:908\u201322.","journal-title":"Nat Med"},{"key":"3141_CR26","doi-asserted-by":"publisher","first-page":"4904","DOI":"10.3748\/wjg.v25.i33.4904","volume":"25","author":"ML Boland","year":"2019","unstructured":"Boland ML, Or\u00f3 D, T\u00f8lb\u00f8l KS, Thrane ST, Nielsen JC, Cohen TS, et al. Towards a standard diet-induced and biopsy-confirmed mouse model of non-alcoholic steatohepatitis: impact of dietary fat source. World J Gastroenterol. 2019;25:4904\u201320.","journal-title":"World J Gastroenterol"},{"key":"3141_CR27","doi-asserted-by":"publisher","first-page":"210","DOI":"10.1186\/s12876-020-01356-2","volume":"20","author":"HH Hansen","year":"2020","unstructured":"Hansen HH, \u00c6gidius HM, Or\u00f3 D, Evers SS, Heeb\u00f8ll S, Eriksen PL, et al. Human translatability of the GAN diet-induced obese mouse model of non-alcoholic steatohepatitis. BMC Gastroenterol. 2020;20:210.","journal-title":"BMC Gastroenterol"},{"key":"3141_CR28","doi-asserted-by":"publisher","first-page":"673","DOI":"10.4254\/wjh.v8.i16.673","volume":"8","author":"MNB Kristiansen","year":"2016","unstructured":"Kristiansen MNB, Veidal SS, Rigbolt KTG, T\u00f8lb\u00f8l KS, Roth J, Jelsing J, et al. Obese diet-induced mouse models of nonalcoholic steatohepatitis-tracking disease by liver biopsy. World J Hepatol. 2016;8:673\u201384.","journal-title":"World J Hepatol"},{"key":"3141_CR29","doi-asserted-by":"publisher","first-page":"1313","DOI":"10.1002\/hep.20701","volume":"41","author":"DE Kleiner","year":"2005","unstructured":"Kleiner DE, Brunt EM, Van Natta M, Behling C, Contos MJ, Cummings OW, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005;41:1313\u201321.","journal-title":"Hepatology"},{"key":"3141_CR30","doi-asserted-by":"publisher","first-page":"179","DOI":"10.3748\/wjg.v24.i2.179","volume":"24","author":"KS T\u00f8lb\u00f8l","year":"2018","unstructured":"T\u00f8lb\u00f8l KS, Kristiansen MN, Hansen HH, Veidal SS, Rigbolt KT, Gillum MP, et al. Metabolic and hepatic effects of liraglutide, obeticholic acid and elafibranor in diet-induced obese mouse models of biopsy-confirmed nonalcoholic steatohepatitis. World J Gastroenterol. 2018;24:179\u201394.","journal-title":"World J Gastroenterol"},{"key":"3141_CR31","doi-asserted-by":"publisher","first-page":"1167","DOI":"10.1111\/cts.13235","volume":"15","author":"MB M\u00f8llerh\u00f8j","year":"2022","unstructured":"M\u00f8llerh\u00f8j MB, Veidal SS, Thrane KT, Or\u00f3 D, Overgaard A, Salinas CG, et al. Hepatoprotective effects of semaglutide, lanifibranor and dietary intervention in the GAN diet-induced obese and biopsy-confirmed mouse model of NASH. Clin Transl Sci. 2022;15:1167\u201386.","journal-title":"Clin Transl Sci"},{"key":"3141_CR32","doi-asserted-by":"publisher","first-page":"799","DOI":"10.1080\/14728222.2021.1992385","volume":"25","author":"W Udomsinprasert","year":"2021","unstructured":"Udomsinprasert W, Sobhonslidsuk A, Jittikoon J, Honsawek S, Chaikledkaew U. Cellular senescence in liver fibrosis: Implications for age-related chronic liver diseases. Expert Opin Ther Targets. 2021;25:799\u2013813.","journal-title":"Expert Opin Ther Targets"},{"key":"3141_CR33","doi-asserted-by":"publisher","first-page":"652","DOI":"10.3390\/ijms23020652","volume":"23","author":"C Engelmann","year":"2022","unstructured":"Engelmann C, Tacke F. The potential role of cellular senescence in non-alcoholic fatty liver disease. Int J Mol Sci. 2022;23:652.","journal-title":"Int J Mol Sci"},{"key":"3141_CR34","doi-asserted-by":"publisher","first-page":"568","DOI":"10.2174\/1389450124666230330135834","volume":"24","author":"X Zhang","year":"2023","unstructured":"Zhang X, Zeng Y, Zhao L, Xu Q, Miao D, Yu F. Targeting hepatic stellate cell death to reverse hepatic fibrosis. Curr Drug Targets. 2023;24:568\u201383.","journal-title":"Curr Drug Targets"},{"key":"3141_CR35","doi-asserted-by":"publisher","first-page":"549","DOI":"10.1016\/j.jhep.2012.10.031","volume":"58","author":"A Aravinthan","year":"2013","unstructured":"Aravinthan A, Scarpini C, Tachtatzis P, Verma S, Penrhyn-Lowe S, Harvey R, et al. Hepatocyte senescence predicts progression in non-alcohol-related fatty liver disease. J Hepatol. 2013;58:549\u201356.","journal-title":"J Hepatol"},{"key":"3141_CR36","doi-asserted-by":"publisher","first-page":"G558","DOI":"10.1152\/ajpgi.00032.2011","volume":"302","author":"X Zhang","year":"2012","unstructured":"Zhang X, Zhou D, Strakovsky R, Zhang Y, Pan YX. Hepatic cellular senescence pathway genes are induced through histone modifications in a diet-induced obese rat model. Am J Physiol Gastrointest Liver Physiol. 2012;302:G558\u201364.","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"key":"3141_CR37","doi-asserted-by":"publisher","first-page":"100301","DOI":"10.1016\/j.jhepr.2021.100301","volume":"3","author":"AS Meijnikman","year":"2021","unstructured":"Meijnikman AS, Herrema H, Scheithauer TPM, Kroon J, Nieuwdorp M, Groen AK. Evaluating causality of cellular senescence in non-alcoholic fatty liver disease. JHEP Rep. 2021;3:100301.","journal-title":"JHEP Rep."},{"key":"3141_CR38","doi-asserted-by":"publisher","first-page":"G378","DOI":"10.1152\/ajpgi.00157.2022","volume":"324","author":"MH Nielsen","year":"2023","unstructured":"Nielsen MH, Gillum MP, Vrang N, Jelsing J, Hansen HH, Feigh M, et al. Hepatoprotective effects of the long-acting fibroblast growth factor 21 analog PF-05231023 in the GAN diet-induced obese and biopsy-confirmed mouse model of nonalcoholic steatohepatitis. Am J Physiol Gastrointest Liver Physiol. 2023;324:G378\u201388.","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"key":"3141_CR39","doi-asserted-by":"publisher","first-page":"e0161","DOI":"10.1097\/HC9.0000000000000161","volume":"7","author":"Y Hosokawa","year":"2023","unstructured":"Hosokawa Y, Hosooka T, Imamori M, Yamaguchi K, Itoh Y, Ogawa W. Adipose tissue insulin resistance exacerbates liver inflammation and fibrosis in a diet-induced NASH model. Hepatol Commun. 2023;7:e0161.","journal-title":"Hepatol Commun"},{"key":"3141_CR40","doi-asserted-by":"publisher","first-page":"15661","DOI":"10.1038\/s41598-022-19459-z","volume":"12","author":"M O\u2019Farrell","year":"2022","unstructured":"O\u2019Farrell M, Duke G, Crowley R, Buckley D, Martins EB, Bhattacharya D, et al. FASN inhibition targets multiple drivers of NASH by reducing steatosis, inflammation and fibrosis in preclinical models. Sci Rep. 2022;12:15661.","journal-title":"Sci Rep"},{"key":"3141_CR41","doi-asserted-by":"publisher","first-page":"e1835","DOI":"10.1038\/cddis.2015.202","volume":"6","author":"J Pfleger","year":"2015","unstructured":"Pfleger J, He M, Abdellatif M. Mitochondrial complex II is a source of the reserve respiratory capacity that is regulated by metabolic sensors and promotes cell survival. Cell Death Dis. 2015;6:e1835.","journal-title":"Cell Death Dis"},{"key":"3141_CR42","doi-asserted-by":"publisher","first-page":"804","DOI":"10.1016\/j.cmet.2011.11.004","volume":"14","author":"NE Sunny","year":"2011","unstructured":"Sunny NE, Parks EJ, Browning JD, Burgess SC. Excessive hepatic mitochondrial TCA cycle and gluconeogenesis in humans with nonalcoholic fatty liver disease. Cell Metab. 2011;14:804\u201310.","journal-title":"Cell Metab"},{"key":"3141_CR43","doi-asserted-by":"publisher","first-page":"739","DOI":"10.1016\/j.cmet.2015.04.004","volume":"21","author":"C Koliaki","year":"2015","unstructured":"Koliaki C, Szendroedi J, Kaul K, Jelenik T, Nowotny P, Jankowiak F, et al. Adaptation of hepatic mitochondrial function in humans with non-alcoholic fatty liver is lost in steatohepatitis. Cell Metab. 2015;21:739\u201346.","journal-title":"Cell Metab"},{"key":"3141_CR44","doi-asserted-by":"publisher","first-page":"917","DOI":"10.1038\/oby.2010.214","volume":"19","author":"DA Buchner","year":"2011","unstructured":"Buchner DA, Yazbek SN, Solinas P, Burrage LC, Morgan MG, Hoppel CL, et al. Increased mitochondrial oxidative phosphorylation in the liver is associated with obesity and insulin resistance. Obesity. 2011;19:917\u201324.","journal-title":"Obesity"},{"key":"3141_CR45","doi-asserted-by":"publisher","DOI":"10.1042\/bj2310439","volume-title":"Elevated hepatic mitochondrial and peroxisomal oxidative capacities in fed and starved adult obese (ob\/ob) mice","author":"LJ Brady","year":"1985","unstructured":"Brady LJ, Brady PS, Romsost DR, Hoppel CL. Elevated hepatic mitochondrial and peroxisomal oxidative capacities in fed and starved adult obese (ob\/ob) mice. 1985."},{"key":"3141_CR46","doi-asserted-by":"publisher","first-page":"6848","DOI":"10.3390\/ijms22136848","volume":"22","author":"ICM Sim\u00f5es","year":"2021","unstructured":"Sim\u00f5es ICM, Amorim R, Teixeira J, Karkucinska-wieckowska A, Carvalho A, Pereira SP, et al. The alterations of mitochondrial function during NAFLD progression\u2014an independent effect of mitochondrial ROS production. Int J Mol Sci. 2021;22:6848.","journal-title":"Int J Mol Sci"},{"key":"3141_CR47","volume-title":"Defective hepatic mitochondrial respiratory chain in patients with nonalcoholic steatohepatitis","author":"M Pirez-Cameras","year":"2003","unstructured":"Pirez-Cameras M, Del P, Juan MA, Rubio C, Castellano G, C~lina F, et al. Defective hepatic mitochondrial respiratory chain in patients with nonalcoholic steatohepatitis. 2003."},{"key":"3141_CR48","doi-asserted-by":"publisher","first-page":"1748","DOI":"10.3748\/wjg.v24.i16.1748","volume":"24","author":"ML Boland","year":"2018","unstructured":"Boland ML, Oldham S, Boland BB, Will S, Lapointe JM, Guionaud S, et al. Nonalcoholic steatohepatitis severity is defined by a failure in compensatory antioxidant capacity in the setting of mitochondrial dysfunction. World J Gastroenterol. 2018;24:1748\u201365.","journal-title":"World J Gastroenterol"},{"key":"3141_CR49","doi-asserted-by":"publisher","first-page":"4855","DOI":"10.3390\/jcm10214855","volume":"10","author":"P Ruiz-Sala","year":"2021","unstructured":"Ruiz-Sala P, Pe\u00f1a-Quintana L. Biochemical markers for the diagnosis of mitochondrial fatty acid oxidation diseases. J Clin Med. 2021;10:4855.","journal-title":"J Clin Med"},{"key":"3141_CR50","doi-asserted-by":"publisher","first-page":"1397","DOI":"10.1016\/j.bbadis.2012.03.009","volume":"1822","author":"MC Hunt","year":"2012","unstructured":"Hunt MC, Siponen MI, Alexson SEH. The emerging role of acyl-CoA thioesterases and acyltransferases in regulating peroxisomal lipid metabolism. Biochim Biophys Acta. 2012;1822:1397\u2013410.","journal-title":"Biochim Biophys Acta"},{"key":"3141_CR51","doi-asserted-by":"publisher","first-page":"19034","DOI":"10.1074\/jbc.RA119.010901","volume":"294","author":"C Bekeova","year":"2019","unstructured":"Bekeova C, Anderson-Pullinger L, Boye K, Boos F, Sharpadskaya Y, Herrmann JM, et al. Multiple mitochondrial thioesterases have distinct tissue and substrate specificity and CoA regulation, suggesting unique functional roles. J Biol Chem. 2019;294:19034\u201347.","journal-title":"J Biol Chem"},{"key":"3141_CR52","doi-asserted-by":"publisher","first-page":"436","DOI":"10.1016\/j.tcb.2018.02.001","volume":"28","author":"A Hernandez-Segura","year":"2018","unstructured":"Hernandez-Segura A, Nehme J, Demaria M. Hallmarks of cellular senescence. Trends Cell Biol. 2018;28:436\u201353.","journal-title":"Trends Cell Biol"},{"key":"3141_CR53","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1146\/annurev-pathol-121808-102144","volume":"5","author":"JP Copp\u00e9","year":"2010","unstructured":"Copp\u00e9 JP, Desprez PY, Krtolica A, Campisi J. The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu Rev Pathol. 2010;5:99\u2013118.","journal-title":"Annu Rev Pathol"},{"key":"3141_CR54","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1186\/s13578-021-00683-5","volume":"11","author":"Y Huang","year":"2021","unstructured":"Huang Y, Yang X, Meng Y, Shao C, Liao J, Li F, et al. The hepatic senescence-associated secretory phenotype promotes hepatocarcinogenesis through Bcl3-dependent activation of macrophages. Cell Biosci. 2021;11:173.","journal-title":"Cell Biosci"},{"key":"3141_CR55","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1038\/cdd.2017.186","volume":"25","author":"J Kale","year":"2018","unstructured":"Kale J, Osterlund EJ, Andrews DW. BCL-2 family proteins: changing partners in the dance towards death. Cell Death Differ. 2018;25:65\u201380.","journal-title":"Cell Death Differ"},{"key":"3141_CR56","doi-asserted-by":"publisher","first-page":"997","DOI":"10.1038\/s41379-019-0218-8","volume":"32","author":"Y Akazawa","year":"2019","unstructured":"Akazawa Y, Nakashima R, Matsuda K, Okamaoto K, Hirano R, Kawasaki H, et al. Detection of DNA damage response in nonalcoholic fatty liver disease via p53-binding protein 1 nuclear expression. Mod Pathol. 2019;32:997\u20131007.","journal-title":"Mod Pathol"},{"key":"3141_CR57","doi-asserted-by":"publisher","first-page":"6198","DOI":"10.3748\/wjg.v12.i38.6198","volume":"12","author":"A Panasiuk","year":"2006","unstructured":"Panasiuk A, Dzieciol J, Panasiuk B, Prokopowicz D. Expression of p53, Bax and Bcl-2 proteins in hepatocytes in non-alcoholic fatty liver disease. World J Gastroenterol. 2006;12:6198\u2013202.","journal-title":"World J Gastroenterol"},{"key":"3141_CR58","doi-asserted-by":"publisher","first-page":"935","DOI":"10.1096\/fj.01-0977com","volume":"16","author":"SU Wiemann","year":"2002","unstructured":"Wiemann SU, Satyanarayana A, Tsahuridu M, Tillmann HL, Zender L, Klempnauer J, et al. Hepatocyte telomere shortening and senescence are general markers of human liver cirrhosis. FASEB J. 2002;16:935\u201342.","journal-title":"FASEB J"},{"key":"3141_CR59","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1016\/j.biocel.2015.11.010","volume":"70","author":"T Xu","year":"2016","unstructured":"Xu T, Ni MM, Xing Li, Li XF, Meng XM, Huang C, et al.\u00a0NLRC5 regulates TGF-\u03b21-induced proliferation and activation of hepatic stellate cells during hepatic fibrosis. Int J Biochem Cell Biol. 2016;70:92\u2013104.","journal-title":"Int J Biochem Cell Biol"},{"key":"3141_CR60","doi-asserted-by":"publisher","first-page":"657","DOI":"10.1016\/j.cell.2008.06.049","volume":"134","author":"V Krizhanovsky","year":"2008","unstructured":"Krizhanovsky V, Yon M, Dickins RA, Hearn S, Simon J, Miething C, et al. Senescence of activated stellate cells limits liver fibrosis. Cell. 2008;134:657\u201367.","journal-title":"Cell"},{"key":"3141_CR61","doi-asserted-by":"publisher","first-page":"e2000383","DOI":"10.1002\/mnfr.202000383","volume":"64","author":"YE Qin","year":"2020","unstructured":"Qin YE, Duan L, He Y, Yuan C, Wang T, Yuan D, et al. Saturated fatty acids promote hepatocytic senecence through regulation of miR-34a\/Cyclin-Dependent Kinase 6. Mol Nutr Food Res. 2020;64:e2000383.","journal-title":"Mol Nutr Food Res"},{"key":"3141_CR62","doi-asserted-by":"publisher","first-page":"558","DOI":"10.1152\/ajpgi.00032.2011","volume":"302","author":"X Zhang","year":"2012","unstructured":"Zhang X, Zhou D, Strakovsky R, Zhang Y, Pan Y-X. Hepatic cellular senescence pathway genes are induced through histone modifications in a diet-induced obese rat model. Am J Physiol Gastrointest Liver Physiol. 2012;302:558\u201364.","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"key":"3141_CR63","doi-asserted-by":"publisher","first-page":"1918","DOI":"10.4161\/cc.20259","volume":"11","author":"EK Daugherity","year":"2012","unstructured":"Daugherity EK, Balmus G, Al Saei A, Moore ES, Abi Abdallah D, Rogers AB, et al. The DNA damage checkpoint protein ATM promotes hepatocellular apoptosis and fibrosis in a mouse model of non-alcoholic fatty liver disease. Cell Cycle. 2012;11:1918\u201328.","journal-title":"Cell Cycle"},{"key":"3141_CR64","doi-asserted-by":"publisher","first-page":"443","DOI":"10.1111\/j.1440-1746.2009.05785.x","volume":"24","author":"GC Farrell","year":"2009","unstructured":"Farrell GC, Larter CZ, Hou JY, Zhang RH, Yeh MM, Williams J, et al. Apoptosis in experimental NASH is associated with p53 activation and TRAIL receptor expression. J Gastroenterol Hepatol. 2009;24:443\u201352.","journal-title":"J Gastroenterol Hepatol"},{"key":"3141_CR65","doi-asserted-by":"publisher","first-page":"837","DOI":"10.1016\/j.jhep.2012.05.013","volume":"57","author":"K Tomita","year":"2012","unstructured":"Tomita K, Teratani T, Suzuki T, Oshikawa T, Yokoyama H, Shimamura K, et al. p53\/p66Shc-mediated signaling contributes to the progression of non-alcoholic steatohepatitis in humans and mice. J Hepatol. 2012;57:837\u201343.","journal-title":"J Hepatol"},{"key":"3141_CR66","doi-asserted-by":"publisher","first-page":"468","DOI":"10.1016\/j.jhepr.2019.10.008","volume":"1","author":"K Hallsworth","year":"2019","unstructured":"Hallsworth K, Adams LA. Lifestyle modification in NAFLD\/NASH: Facts and figures. JHEP Reports. 2019;1:468\u201379.","journal-title":"JHEP Reports"},{"key":"3141_CR67","doi-asserted-by":"publisher","first-page":"406","DOI":"10.1124\/jpet.122.001440","volume":"384","author":"A Kayed","year":"2023","unstructured":"Kayed A, Melander SA, Khan S, Andreassen KV, Karsdal MA, Henriksen K. The effects of dual GLP-1\/Glucagon receptor agonists with different receptor selectivity in mouse models of obesity and nonalcoholic steatohepatitis. J Pharmacol Exp Ther. 2023;384:406\u201316.","journal-title":"J Pharmacol Exp Ther"},{"key":"3141_CR68","doi-asserted-by":"publisher","first-page":"349","DOI":"10.1016\/j.dld.2004.11.009","volume":"37","author":"G Carpino","year":"2005","unstructured":"Carpino G, Morini S, Ginanni Corradini S, Franchitto A, Merli M, Siciliano M, et al. Alpha-SMA expression in hepatic stellate cells and quantitative analysis of hepatic fibrosis in cirrhosis and in recurrent chronic hepatitis after liver transplantation. Dig Liver Dis. 2005;37:349\u201356.","journal-title":"Dig Liver Dis"},{"key":"3141_CR69","doi-asserted-by":"publisher","first-page":"E969","DOI":"10.1152\/ajpendo.00497.2007","volume":"294","author":"M Stefanovic-Racic","year":"2008","unstructured":"Stefanovic-Racic M, Perdomo G, Mantell BS, Sipula IJ, Brown NF, O\u2019Doherty RM. A moderate increase in carnitine palmitoyltransferase 1a activity is sufficient to substantially reduce hepatic triglyceride levels. Am J Physiol Endocrinol Metab. 2008;294:E969\u201377.","journal-title":"Am J Physiol Endocrinol Metab"},{"key":"3141_CR70","doi-asserted-by":"publisher","first-page":"1253","DOI":"10.1126\/science.aaa0672","volume":"347","author":"RJ Perry","year":"2015","unstructured":"Perry RJ, Zhang D, Zhang XM, Boyer JL, Shulman GI. Controlled-release mitochondrial protonophore reverses diabetes and steatohepatitis in rats. Science. 2015;347:1253\u20136.","journal-title":"Science"},{"key":"3141_CR71","doi-asserted-by":"publisher","first-page":"2931","DOI":"10.1038\/s41467-022-30629-5","volume":"13","author":"JS Pedersen","year":"2022","unstructured":"Pedersen JS, Rygg MO, Chr\u00f8is K, Sustarsic EG, Gerhart-Hines Z, Wever Albrechtsen NJ, et al. Influence of NAFLD and bariatric surgery on hepatic and adipose tissue mitochondrial biogenesis and respiration. Nat Commun. 2022;13:2931.","journal-title":"Nat Commun"},{"key":"3141_CR72","doi-asserted-by":"publisher","first-page":"3349","DOI":"10.1113\/jphysiol.2012.230185","volume":"590","author":"S Larsen","year":"2012","unstructured":"Larsen S, Nielsen J, Hansen CN, Nielsen LB, Wibrand F, Stride N, et al. Biomarkers of mitochondrial content in skeletal muscle of healthy young human subjects. J Physiol. 2012;590:3349\u201360.","journal-title":"J Physiol"}],"container-title":["BMC Gastroenterology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12876-024-03141-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12876-024-03141-x\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12876-024-03141-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,2,5]],"date-time":"2024-02-05T04:04:49Z","timestamp":1707105889000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmcgastroenterol.biomedcentral.com\/articles\/10.1186\/s12876-024-03141-x"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,2,2]]},"references-count":72,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["3141"],"URL":"https:\/\/doi.org\/10.1186\/s12876-024-03141-x","relation":{},"ISSN":["1471-230X"],"issn-type":[{"value":"1471-230X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,2,2]]},"assertion":[{"value":"4 October 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 January 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 February 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"All experiments complied with the provisions of the Danish Animal Experiments Act and were approved by the Danish Animal Experiments Council (license #2013-15-2934-00784). All animal experiments conducted were approved by the internal Gubra Animal Welfare Body and were in full compliance with internationally accepted principles for the care and use of laboratory animals and conform to the Animal Research: Reporting of In Vivo Experiments (ARRIVE) guidelines.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"DO, EAR, MRM, ANM, MF and HHH are employed by Gubra. DO, MRM, ANM, MF and HHH are shareholders in Gubra. MFJ was previously employed at Gubra and now employed by University of Copenhagen. CZ was previously employed by Gubra and now employed by Novo Nordisk A\/S. JN is employed by Novo Nordisk. No other potential conflicts of interest were reported.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"59"}}