{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,5]],"date-time":"2025-11-05T06:49:13Z","timestamp":1762325353894,"version":"3.37.3"},"reference-count":46,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2022,7,8]],"date-time":"2022-07-08T00:00:00Z","timestamp":1657238400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2022,7,8]],"date-time":"2022-07-08T00:00:00Z","timestamp":1657238400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Bristol Myers Squibb"},{"DOI":"10.13039\/501100007132","name":"Otsuka Pharmaceutical","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100007132","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>I\u03baB\u03b6 is a transcriptional regulator that augments inflammatory responses from the Toll-like receptor or interleukin signaling. These innate immune responses contribute to the progression of nonalcoholic fatty liver disease (NAFLD); however, the role of I\u03baB\u03b6 in the pathogenesis of NAFLD remains elusive. We investigated whether I\u03baB\u03b6 was involved in the progression of NAFLD in mice. We generated hepatocyte-specific I\u03baB\u03b6-deficient mice (<jats:italic>Alb-Cre; Nfkbiz<\/jats:italic><jats:sup><jats:italic>fl<\/jats:italic>\/<jats:italic>fl<\/jats:italic><\/jats:sup>) by crossing <jats:italic>Nfkbiz<\/jats:italic><jats:sup><jats:italic>fl<\/jats:italic>\/<jats:italic>fl<\/jats:italic><\/jats:sup> mice with <jats:italic>Alb-Cre<\/jats:italic> transgenic mice. NAFLD was induced by feeding the mice a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD). CDAHFD-induced I\u03baB\u03b6 expression in the liver was observed in <jats:italic>Nfkbiz<\/jats:italic><jats:sup><jats:italic>fl<\/jats:italic>\/<jats:italic>fl<\/jats:italic><\/jats:sup> mice, but not in <jats:italic>Alb-Cre; Nfkbiz<\/jats:italic><jats:sup><jats:italic>fl<\/jats:italic>\/<jats:italic>fl<\/jats:italic><\/jats:sup> mice. Contrary to our initial expectation, I\u03baB\u03b6 deletion in hepatocytes accelerated the progression of NAFLD after CDAHFD treatment. Although the increased expression of inflammatory cytokines and apoptosis-related proteins by CDAHFD remained unchanged between <jats:italic>Nfkbiz<\/jats:italic><jats:sup><jats:italic>fl<\/jats:italic>\/<jats:italic>fl<\/jats:italic><\/jats:sup> and <jats:italic>Alb-Cre; Nfkbiz<\/jats:italic><jats:sup><jats:italic>fl<\/jats:italic>\/<jats:italic>fl<\/jats:italic><\/jats:sup> mice, early-stage steatosis of the liver was significantly augmented in <jats:italic>Alb-Cre; Nfkbiz<\/jats:italic><jats:sup><jats:italic>fl<\/jats:italic>\/<jats:italic>fl<\/jats:italic><\/jats:sup> mice. Overexpression of I\u03baB\u03b6 in hepatocytes via the adeno-associated virus vector attenuated liver steatosis caused by the CDAHFD in wild-type C57BL\/6 mice. This preventive effect of I\u03baB\u03b6 overexpression on steatosis was not observed without transcriptional activity. Microarray analysis revealed a correlation between I\u03baB\u03b6 expression and the changes of factors related to triglyceride biosynthesis and lipoprotein uptake. Our data suggest that hepatic I\u03baB\u03b6 attenuates the progression of NAFLD possibly through the regulation of the factors related to triglyceride metabolism.<\/jats:p>","DOI":"10.1038\/s41598-022-15840-0","type":"journal-article","created":{"date-parts":[[2022,7,8]],"date-time":"2022-07-08T11:03:32Z","timestamp":1657278212000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["I\u03baB\u03b6 regulates the development of nonalcoholic fatty liver disease through the attenuation of hepatic steatosis in mice"],"prefix":"10.1038","volume":"12","author":[{"given":"Hideki","family":"Ishikawa","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Morisada","family":"Hayakawa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nemekhbayar","family":"Baatartsogt","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nao","family":"Kakizawa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiromi","family":"Ohto-Ozaki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takashi","family":"Maruyama","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kouichi","family":"Miura","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Koichi","family":"Suzuki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Toshiki","family":"Rikiyama","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tsukasa","family":"Ohmori","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2022,7,8]]},"reference":[{"key":"15840_CR1","doi-asserted-by":"publisher","first-page":"896","DOI":"10.1016\/j.jhep.2018.05.036","volume":"69","author":"C Estes","year":"2018","unstructured":"Estes, C. et al. Modeling NAFLD disease burden in China, France, Germany, Italy, Japan, Spain, United Kingdom, and United States for the period 2016\u20132030. J. Hepatol. 69, 896\u2013904 (2018).","journal-title":"J. Hepatol."},{"key":"15840_CR2","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1002\/hep.28431","volume":"64","author":"ZM Younossi","year":"2016","unstructured":"Younossi, Z. M. et al. Global epidemiology of nonalcoholic fatty liver disease-meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 64, 73\u201384 (2016).","journal-title":"Hepatology"},{"key":"15840_CR3","doi-asserted-by":"publisher","first-page":"531","DOI":"10.1016\/j.jhep.2018.10.033","volume":"70","author":"ZM Younossi","year":"2019","unstructured":"Younossi, Z. M. Non-alcoholic fatty liver disease\u2014A global public health perspective. J. Hepatol. 70, 531\u2013544 (2019).","journal-title":"J. Hepatol."},{"key":"15840_CR4","doi-asserted-by":"publisher","first-page":"1313","DOI":"10.1002\/hep.20701","volume":"41","author":"DE Kleiner","year":"2005","unstructured":"Kleiner, D. E. et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 41, 1313\u20131321 (2005).","journal-title":"Hepatology"},{"key":"15840_CR5","doi-asserted-by":"publisher","first-page":"2263","DOI":"10.1001\/jama.2015.5370","volume":"313","author":"ME Rinella","year":"2015","unstructured":"Rinella, M. E. Nonalcoholic fatty liver disease: A systematic review. JAMA 313, 2263 (2015).","journal-title":"JAMA"},{"key":"15840_CR6","doi-asserted-by":"publisher","first-page":"328","DOI":"10.1002\/hep.29367","volume":"67","author":"N Chalasani","year":"2018","unstructured":"Chalasani, N. et al. The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases. Hepatology 67, 328\u2013357 (2018).","journal-title":"Hepatology"},{"key":"15840_CR7","doi-asserted-by":"publisher","first-page":"411","DOI":"10.1038\/s41575-019-0145-7","volume":"16","author":"QM Anstee","year":"2019","unstructured":"Anstee, Q. M., Reeves, H. L., Kotsiliti, E., Govaere, O. & Heikenwalder, M. From NASH to HCC: Current concepts and future challenges. Nat. Rev. Gastroenterol. Hepatol. 16, 411\u2013428 (2019).","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"15840_CR8","doi-asserted-by":"publisher","first-page":"1265","DOI":"10.1016\/j.jhep.2017.07.027","volume":"67","author":"H Hagstr\u00f6m","year":"2017","unstructured":"Hagstr\u00f6m, H. et al. Fibrosis stage but not NASH predicts mortality and time to development of severe liver disease in biopsy-proven NAFLD. J. Hepatol. 67, 1265\u20131273 (2017).","journal-title":"J. Hepatol."},{"key":"15840_CR9","doi-asserted-by":"publisher","first-page":"1138","DOI":"10.1136\/gutjnl-2017-313884","volume":"66","author":"LA Adams","year":"2017","unstructured":"Adams, L. A., Anstee, Q. M., Tilg, H. & Targher, G. Non-alcoholic fatty liver disease and its relationship with cardiovascular disease and other extrahepatic diseases. Gut 66, 1138\u20131153 (2017).","journal-title":"Gut"},{"key":"15840_CR10","first-page":"323","volume":"8","author":"W Ding","year":"2015","unstructured":"Ding, W., Fan, J. & Qin, J. Association between nonalcoholic fatty liver disease and colorectal adenoma: A systematic review and meta-analysis. Int. J. Clin. Med. 8, 323\u2013333 (2015).","journal-title":"Int. J. Clin. Med."},{"key":"15840_CR11","doi-asserted-by":"publisher","first-page":"140","DOI":"10.1016\/j.jhep.2017.09.012","volume":"68","author":"G-A Kim","year":"2018","unstructured":"Kim, G.-A. et al. Association between non-alcoholic fatty liver disease and cancer incidence rate. J. Hepatol. 68, 140\u2013146 (2018).","journal-title":"J. Hepatol."},{"key":"15840_CR12","doi-asserted-by":"publisher","first-page":"362","DOI":"10.1007\/s00535-017-1415-1","volume":"53","author":"Y Sumida","year":"2018","unstructured":"Sumida, Y. & Yoneda, M. Current and future pharmacological therapies for NAFLD\/NASH. J. Gastroenterol. 53, 362\u2013376 (2018).","journal-title":"J. Gastroenterol."},{"key":"15840_CR13","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1016\/j.jcmgh.2019.04.007","volume":"8","author":"WP Esler","year":"2019","unstructured":"Esler, W. P. & Bence, K. K. Metabolic targets in nonalcoholic fatty liver disease. Cell Mol. Gastroenterol. Hepatol. 8, 247\u2013267 (2019).","journal-title":"Cell Mol. Gastroenterol. Hepatol."},{"key":"15840_CR14","doi-asserted-by":"publisher","first-page":"478","DOI":"10.1002\/hep4.1479","volume":"4","author":"G Parthasarathy","year":"2020","unstructured":"Parthasarathy, G., Revelo, X. & Malhi, H. Pathogenesis of nonalcoholic steatohepatitis: An overview. Hepatol. Commun. 4, 478\u2013492 (2020).","journal-title":"Hepatol. Commun."},{"key":"15840_CR15","doi-asserted-by":"publisher","first-page":"1836","DOI":"10.1002\/hep.24001","volume":"52","author":"H Tilg","year":"2010","unstructured":"Tilg, H. & Moschen, A. R. Evolution of inflammation in nonalcoholic fatty liver disease: The multiple parallel hits hypothesis. Hepatology 52, 1836\u20131846 (2010).","journal-title":"Hepatology"},{"key":"15840_CR16","doi-asserted-by":"publisher","first-page":"108","DOI":"10.1038\/nrgastro.2010.213","volume":"8","author":"T Luedde","year":"2011","unstructured":"Luedde, T. & Schwabe, R. F. NF-\u03baB in the liver\u2014Linking injury, fibrosis and hepatocellular carcinoma. Nat. Rev. Gastroenterol. Hepatol. 8, 108\u2013118 (2011).","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"15840_CR17","doi-asserted-by":"publisher","first-page":"17023","DOI":"10.1038\/sigtrans.2017.23","volume":"2","author":"T Liu","year":"2017","unstructured":"Liu, T., Zhang, L., Joo, D. & Sun, S.-C. NF-\u03baB signaling in inflammation. Sig. Transduct. Target. Ther. 2, 17023 (2017).","journal-title":"Sig. Transduct. Target. Ther."},{"key":"15840_CR18","doi-asserted-by":"publisher","first-page":"1117","DOI":"10.1002\/hep.25711","volume":"56","author":"Y Sunami","year":"2012","unstructured":"Sunami, Y. et al. Hepatic activation of IKK\/NF\u03baB signaling induces liver fibrosis via macrophage-mediated chronic inflammation. Hepatology 56, 1117\u20131128 (2012).","journal-title":"Hepatology"},{"key":"15840_CR19","doi-asserted-by":"publisher","first-page":"1663","DOI":"10.1053\/j.gastro.2005.09.004","volume":"129","author":"A dele Pe\u00f1a","year":"2005","unstructured":"dele Pe\u00f1a, A. et al. NF-\u03baB activation, rather than TNF, mediates hepatic inflammation in a murine dietary model of steatohepatitis. Gastroenterology 129, 1663\u20131674 (2005).","journal-title":"Gastroenterology"},{"key":"15840_CR20","doi-asserted-by":"publisher","first-page":"545","DOI":"10.1038\/nri.2017.52","volume":"17","author":"S-C Sun","year":"2017","unstructured":"Sun, S.-C. The non-canonical NF-\u03baB pathway in immunity and inflammation. Nat. Rev. Immunol. 17, 545\u2013558 (2017).","journal-title":"Nat. Rev. Immunol."},{"key":"15840_CR21","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1016\/j.imlet.2016.01.006","volume":"171","author":"M Annemann","year":"2016","unstructured":"Annemann, M. et al. Atypical I\u03baB proteins in immune cell differentiation and function. Immunol. Lett. 171, 26\u201335 (2016).","journal-title":"Immunol. Lett."},{"key":"15840_CR22","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1038\/nature02738","volume":"430","author":"M Yamamoto","year":"2004","unstructured":"Yamamoto, M. et al. Regulation of Toll\/IL-1-receptor-mediated gene expression by the inducible nuclear protein IkappaBzeta. Nature 430, 5 (2004).","journal-title":"Nature"},{"key":"15840_CR23","doi-asserted-by":"publisher","first-page":"2033","DOI":"10.4049\/jimmunol.1900315","volume":"204","author":"H Ohto-Ozaki","year":"2020","unstructured":"Ohto-Ozaki, H. et al. Induction of I\u03baB\u03b6 augments cytokine and chemokine production by IL-33 in mast cells. J. Immunol. 204, 2033\u20132042 (2020).","journal-title":"J. Immunol."},{"key":"15840_CR24","doi-asserted-by":"publisher","first-page":"443","DOI":"10.1093\/intimm\/dxw011","volume":"28","author":"R Muromoto","year":"2016","unstructured":"Muromoto, R. et al. IL-17A plays a central role in the expression of psoriasis signature genes through the induction of I\u03baB-\u03b6 in keratinocytes. Int. Immunol. 28, 443\u2013452 (2016).","journal-title":"Int. Immunol."},{"key":"15840_CR25","doi-asserted-by":"publisher","first-page":"10088","DOI":"10.1073\/pnas.1801377115","volume":"115","author":"A M\u00fcller","year":"2018","unstructured":"M\u00fcller, A. et al. I\u03baB\u03b6 is a key transcriptional regulator of IL-36-driven psoriasis-related gene expression in keratinocytes. Proc. Natl. Acad. Sci. U. S. A. 115, 10088\u201310093 (2018).","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"15840_CR26","doi-asserted-by":"publisher","first-page":"450","DOI":"10.1016\/j.immuni.2012.11.016","volume":"38","author":"A Okuma","year":"2013","unstructured":"Okuma, A. et al. Enhanced apoptosis by disruption of the STAT3-I\u03baB-\u03b6 signaling pathway in epithelial cells induces Sj\u00f6gren\u2019s syndrome-like autoimmune disease. Immunity 38, 450\u2013460 (2013).","journal-title":"Immunity"},{"key":"15840_CR27","doi-asserted-by":"publisher","first-page":"260","DOI":"10.1038\/s41586-019-1856-1","volume":"577","author":"N Kakiuchi","year":"2020","unstructured":"Kakiuchi, N. et al. Frequent mutations that converge on the NFKBIZ pathway in ulcerative colitis. Nature 577, 260\u2013265 (2020).","journal-title":"Nature"},{"key":"15840_CR28","doi-asserted-by":"publisher","first-page":"349","DOI":"10.1038\/s41575-018-0009-6","volume":"15","author":"S Schuster","year":"2018","unstructured":"Schuster, S., Cabrera, D., Arrese, M. & Feldstein, A. E. Triggering and resolution of inflammation in NASH. Nat. Rev. Gastroenterol. Hepatol. 15, 349\u2013364 (2018).","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"15840_CR29","doi-asserted-by":"publisher","first-page":"149","DOI":"10.5009\/gnl.2012.6.2.149","volume":"6","author":"GC Farrell","year":"2012","unstructured":"Farrell, G. C., van Rooyen, D., Gan, L. & Chitturi, S. NASH is an Infl ammatory disorder: Pathogenic, prognostic and therapeutic implications. Gut. Liver 6, 149\u2013171 (2012).","journal-title":"Gut. Liver"},{"key":"15840_CR30","doi-asserted-by":"publisher","first-page":"323","DOI":"10.1053\/j.gastro.2010.03.052","volume":"139","author":"K Miura","year":"2010","unstructured":"Miura, K. et al. Toll-like receptor 9 promotes steatohepatitis by induction of interleukin-1\u03b2 in mice. Gastroenterology 139, 323-334.e7 (2010).","journal-title":"Gastroenterology"},{"key":"15840_CR31","doi-asserted-by":"publisher","first-page":"7444","DOI":"10.1074\/jbc.M412738200","volume":"280","author":"M Motoyama","year":"2005","unstructured":"Motoyama, M., Yamazaki, S., Eto-Kimura, A., Takeshige, K. & Muta, T. Positive and negative regulation of nuclear factor-\u03baB-mediated transcription by I\u03baB-\u03b6, an inducible nuclear protein. J Biol Chem 280, 7444\u20137451 (2005).","journal-title":"J Biol Chem"},{"key":"15840_CR32","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1016\/S0014-5793(00)02185-2","volume":"485","author":"H Kitamura","year":"2000","unstructured":"Kitamura, H., Kanehira, K., Okita, K., Morimatsu, M. & Saito, M. MAIL, a novel nuclear I\u03baB protein that potentiates LPS-induced IL-6 production. FEBS Lett. 485, 53\u201356 (2000).","journal-title":"FEBS Lett."},{"key":"15840_CR33","doi-asserted-by":"publisher","first-page":"27657","DOI":"10.1074\/jbc.M103426200","volume":"276","author":"S Yamazaki","year":"2001","unstructured":"Yamazaki, S., Muta, T. & Takeshige, K. A novel I\u03baB protein, I\u03baB-\u03b6, induced by proinflammatory stimuli, negatively regulates nuclear factor-\u03baB in the nuclei. J. Biol. Chem. 276, 27657\u201327662 (2001).","journal-title":"J. Biol. Chem."},{"key":"15840_CR34","doi-asserted-by":"publisher","first-page":"E1195","DOI":"10.1152\/ajpendo.90958.2008","volume":"296","author":"K Takeuchi","year":"2009","unstructured":"Takeuchi, K. & Reue, K. Biochemistry, physiology, and genetics of GPAT, AGPAT, and lipin enzymes in triglyceride synthesis. Am. J. Physio Endocrinol. Metab. 296, E1195\u2013E1209 (2009).","journal-title":"Am. J. Physio Endocrinol. Metab."},{"key":"15840_CR35","doi-asserted-by":"publisher","first-page":"1519","DOI":"10.1126\/science.1204265","volume":"332","author":"JC Cohen","year":"2011","unstructured":"Cohen, J. C., Horton, J. D. & Hobbs, H. H. Human fatty liver disease: Old questions and new insights. Science 332, 1519\u20131523 (2011).","journal-title":"Science"},{"key":"15840_CR36","doi-asserted-by":"publisher","first-page":"1249","DOI":"10.1016\/j.bbalip.2010.07.008","volume":"1801","author":"M Bou Khalil","year":"2010","unstructured":"Bou Khalil, M., Blais, A., Figeys, D. & Yao, Z. Lipin\u2014The bridge between hepatic glycerolipid biosynthesis and lipoprotein metabolism. Biochim. Biophys. Acta 1801, 1249\u20131259 (2010).","journal-title":"Biochim. Biophys. Acta"},{"key":"15840_CR37","doi-asserted-by":"publisher","first-page":"1953","DOI":"10.1002\/hep.26589","volume":"58","author":"M Hu","year":"2013","unstructured":"Hu, M. et al. Hepatic-specific lipin-1 deficiency exacerbates experimental alcohol-induced steatohepatitis in mice. Hepatology 58, 1953\u20131963 (2013).","journal-title":"Hepatology"},{"key":"15840_CR38","doi-asserted-by":"publisher","first-page":"14230","DOI":"10.1038\/s41598-018-32586-w","volume":"8","author":"T Arai","year":"2018","unstructured":"Arai, T., Tanaka, M. & Goda, N. HIF-1-dependent lipin1 induction prevents excessive lipid accumulation in choline-deficient diet-induced fatty liver. Sci. Rep. 8, 14230 (2018).","journal-title":"Sci. Rep."},{"key":"15840_CR39","doi-asserted-by":"publisher","first-page":"S47","DOI":"10.1016\/j.jhep.2014.12.012","volume":"62","author":"CD Byrne","year":"2015","unstructured":"Byrne, C. D. & Targher, G. NAFLD: A multisystem disease. J. Hepatol. 62, S47\u2013S64 (2015).","journal-title":"J. Hepatol."},{"key":"15840_CR40","doi-asserted-by":"publisher","first-page":"460","DOI":"10.1053\/j.gastro.2003.10.065","volume":"126","author":"HB El-serag","year":"2004","unstructured":"El-serag, H. B., Tran, T. & Everhart, J. E. Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma. Gastroenterology 126, 460\u2013468 (2004).","journal-title":"Gastroenterology"},{"key":"15840_CR41","doi-asserted-by":"publisher","first-page":"343","DOI":"10.1038\/nrgastro.2017.32","volume":"14","author":"NL Gluchowski","year":"2017","unstructured":"Gluchowski, N. L., Becuwe, M., Walther, T. C. & Farese, R. V. Lipid droplets and liver disease: From basic biology to clinical implications. Nat. Rev. Gastroenterol. Hepatol. 14, 343\u2013355 (2017).","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"15840_CR42","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1038\/nrgastro.2016.147","volume":"14","author":"H Tilg","year":"2017","unstructured":"Tilg, H., Moschen, A. R. & Roden, M. NAFLD and diabetes mellitus. Nat. Rev. Gastroenterol. Hepatol. 14, 32\u201342 (2017).","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"15840_CR43","doi-asserted-by":"publisher","first-page":"908","DOI":"10.1038\/s41591-018-0104-9","volume":"24","author":"SL Friedman","year":"2018","unstructured":"Friedman, S. L., Neuschwander-Tetri, B. A., Rinella, M. & Sanyal, A. J. Mechanisms of NAFLD development and therapeutic strategies. Nat. Med. 24, 908\u2013922 (2018).","journal-title":"Nat. Med."},{"key":"15840_CR44","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1002\/(SICI)1526-968X(200002)26:2<149::AID-GENE16>3.0.CO;2-V","volume":"26","author":"C Postic","year":"2000","unstructured":"Postic, C. & Magnuson, M. A. DNA excision in liver by an albumin-Cre transgene occurs progressively with age. Genesis 26, 149\u2013150 (2000).","journal-title":"Genesis"},{"key":"15840_CR45","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1111\/iep.12008","volume":"94","author":"M Matsumoto","year":"2013","unstructured":"Matsumoto, M. et al. An improved mouse model that rapidly develops fibrosis in non-alcoholic steatohepatitis. Int. J. Exp. Path. 94, 93\u2013103 (2013).","journal-title":"Int. J. Exp. Path."},{"key":"15840_CR46","doi-asserted-by":"publisher","first-page":"4159","DOI":"10.1038\/s41598-017-04625-5","volume":"7","author":"T Ohmori","year":"2017","unstructured":"Ohmori, T. et al. CRISPR\/Cas9-mediated genome editing via postnatal administration of AAV vector cures haemophilia B mice. Sci. Rep. 7, 4159 (2017).","journal-title":"Sci. Rep."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-022-15840-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-022-15840-0","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-022-15840-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,25]],"date-time":"2022-11-25T07:03:56Z","timestamp":1669359836000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-022-15840-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,8]]},"references-count":46,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2022,12]]}},"alternative-id":["15840"],"URL":"https:\/\/doi.org\/10.1038\/s41598-022-15840-0","relation":{},"ISSN":["2045-2322"],"issn-type":[{"type":"electronic","value":"2045-2322"}],"subject":[],"published":{"date-parts":[[2022,7,8]]},"assertion":[{"value":"31 January 2022","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 June 2022","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 July 2022","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"M.H. received a research grant from Bristol Myers Squibb for this study. T.O. received grant support from Otsuka Pharmaceutical for the study. All other authors declare no competing financial interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"11634"}}