{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T14:38:11Z","timestamp":1787755091933,"version":"build-2784847793"},"reference-count":28,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2022,5,23]],"date-time":"2022-05-23T00:00:00Z","timestamp":1653264000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Alcoholism Clin &amp;amp; Exp Res"],"published-print":{"date-parts":[[2022,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Nonalcoholic steatohepatitis is the inflammatory subtype of nonalcoholic fatty liver disease with a high risk of progression to liver fibrosis. We investigated metabolic steatohepatitis with advanced liver fibrosis in apolipoprotein E\/low\u2010density lipoprotein receptor double\u2010knockout (AL) mice fed a co\u2010diet of ethanol with a low\u2010carbohydrate\u2013high\u2010protein\u2010high\u2010fat atherogenic diet (AD) for 16\u00a0weeks. We also examined the underlying mechanisms, especially hepatic sympathetic activation, involved in the effects.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We maintained 12\u2010week\u2010old male AL mice on AD and a standard chow diet (SCD) with or without ethanol treatment for 16\u00a0weeks. Age\u2010matched male C57BL\/6J mice on SCD without ethanol treatment served as controls. We conducted blood biochemical, histopathological, and fluorescence immunohistochemical, and reverse transcriptase polymerase chain reaction studies.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>AL mice showed significant hyperlipidemia. AD induced increased body weight, hepatic steatosis, and hepatic damage; ethanol and the AD co\u2010diet resulted in hepatic sympathetic activation accompanied by hepatic steatosis, lobular inflammation, bridging fibrosis, and hepatic damage. Hepatic Kupffer cells (KCs) and hepatic stellate cells (HSCs), which showed sympathetic activation, produced 4.4\u2010 to 9.4\u2010fold more inflammatory factors (KC and KC\u2010derived tumor necrosis factor\u2010\u03b1, and chemokine [C\u2010C motif] ligand 2) and 2.0\u2010 to 32.0\u2010fold more fibrosis factors (HSC and HSC\u2010derived transforming growth factor \u03b21 and collagen 1a1); all <jats:italic>p<\/jats:italic>\u00a0&lt;\u00a00.05 vs. controls.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>We created a model of metabolic steatohepatitis with advanced liver fibrosis from coexisting hyperlipidemia and hepatic sympathetic activation in AL mice on a co\u2010diet of ethanol and AD. KCs and HSCs became the cellular targets of hepatic sympathetic activation, which could play a role in the initiation and progression of metabolic steatohepatitis with advanced liver fibrosis.<\/jats:p><\/jats:sec>","DOI":"10.1111\/acer.14852","type":"journal-article","created":{"date-parts":[[2022,5,2]],"date-time":"2022-05-02T04:35:22Z","timestamp":1651466122000},"page":"1192-1203","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Chronic ethanol consumption plus an atherogenic diet cause metabolic steatohepatitis with advanced liver fibrosis in apolipoprotein E\/low\u2010density lipoprotein receptor double\u2010knockout mice"],"prefix":"10.1111","volume":"46","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3857-5259","authenticated-orcid":false,"given":"Jinyao","family":"Liu","sequence":"first","affiliation":[{"name":"Yamaguchi University Graduate School of Medicine  Ube Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yumiko","family":"Oba","sequence":"additional","affiliation":[{"name":"Yamaguchi University Graduate School of Medicine  Ube Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seiko","family":"Yamano","sequence":"additional","affiliation":[{"name":"Science Research Center Institute of Life Science and Medicine Yamaguchi University  Ube 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