{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T02:10:46Z","timestamp":1777428646849,"version":"3.51.4"},"reference-count":57,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2023,6,18]],"date-time":"2023-06-18T00:00:00Z","timestamp":1687046400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["P20GM103549"],"award-info":[{"award-number":["P20GM103549"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["P30GM118247"],"award-info":[{"award-number":["P30GM118247"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Alcohol: Clinical and Experimental Research"],"published-print":{"date-parts":[[2023,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Chronic ethanol overconsumption promotes alcohol\u2010associated liver disease (ALD), characterized by hepatocyte injury, inflammation, hepatic stellate cell (HSC) activation, and fibrosis. Hyaluronan (HA) concentration is greater in livers and blood from advanced ALD patients than patients with advanced non\u2010ALD. In the liver, HSCs are the major HA producers. The relationship between ethanol, HA, and HSC activation is incompletely understood. Thus, here, we tested the hypothesis that ethanol enhances HSC activation in a HA\u2010dependent manner.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Liver tissue microarrays (TMAs) containing steatotic livers from donors with or without a history of alcohol consumption were used to measure HA and collagen content. Mice were fed a moderate (2%, v\/v) ethanol\u2010containing diet or pair\u2010fed control diet for 2\u2009days, after which they were given a single carbon tetrachloride (CCl<jats:sub>4<\/jats:sub>) injection. To inhibit HA synthesis, we provided 4\u2010methylumbelliferone (4MU) daily. We used LX2 cells, a human HSC cell line, to determine the impact ethanol had on LPS responses, with or without concurrent 4MU exposure.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>CCl<jats:sub>4<\/jats:sub> induced liver injury, but it did not differ between ethanol or control diet fed mice with or without 4MU treatment. Ethanol feeding enhanced CCl<jats:sub>4<\/jats:sub>\u2010induced hepatic HA content, which was paralleled by HA synthase (<jats:italic>Has<\/jats:italic>)<jats:italic>2<\/jats:italic> transcript abundance; 4MU treatment normalized both. Consistently, HSC activation, assessed by measuring \u03b1SMA mRNA and protein, was induced by CCl<jats:sub>4<\/jats:sub> exposure, enhanced by ethanol feeding, and normalized by 4MU. Hepatic transcripts, but not protein, for <jats:italic>Ccl2<\/jats:italic> were enhanced by ethanol feeding and normalized by 4MU exposure. Finally, ethanol\u2010exposed LX2 cells made more LPS\u2010stimulated <jats:italic>CCL2<\/jats:italic> mRNA and protein than cells not exposed to ethanol; 4MU prevented this.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>These data show that ethanol augments HSC activation through HA synthesis and enhances hepatic profibrogenic features. Therefore, targeting HSC HA production could potentially attenuate liver disease in ALD patients.<\/jats:p><\/jats:sec>","DOI":"10.1111\/acer.15127","type":"journal-article","created":{"date-parts":[[2023,6,19]],"date-time":"2023-06-19T01:45:06Z","timestamp":1687139106000},"page":"1544-1559","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Hyaluronan synthesis inhibition normalizes ethanol\u2010enhanced hepatic stellate cell activation"],"prefix":"10.1111","volume":"47","author":[{"given":"Manasi","family":"Kotulkar","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Toxicology and Therapeutics University of Kansas Medical Center  Kansas City Kansas USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dakota R.","family":"Robarts","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Toxicology and Therapeutics University of Kansas Medical Center  Kansas City 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