{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T19:03:51Z","timestamp":1776366231816,"version":"3.51.2"},"reference-count":40,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2023,3,1]],"date-time":"2023-03-01T00:00:00Z","timestamp":1677628800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institutes of Health","award":["K01AA024809"],"award-info":[{"award-number":["K01AA024809"]}]},{"name":"National Institutes of Health","award":["R03 AA028585"],"award-info":[{"award-number":["R03 AA028585"]}]},{"name":"University of Texas at Dallas Office of Research and Innovation","award":["K01AA024809"],"award-info":[{"award-number":["K01AA024809"]}]},{"name":"University of Texas at Dallas Office of Research and Innovation","award":["R03 AA028585"],"award-info":[{"award-number":["R03 AA028585"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Accumulating evidence has demonstrated the association between alcohol overconsumption and the development of insulin resistance. However, the underlying mechanisms are not completely understood. To investigate the requirement and sufficiency of hepatocyte toll-like receptor 4 (TLR4) in alcohol-induced insulin resistance, we used two mouse models (Tlr4fl\/fl and Tlr4LoxTB) that allow ablation of TLR4 only in hepatocytes (Tlr4LKO) and restoration of endogenous TLR4 expression in hepatocytes on a TLR4-null background (Tlr4LoxTB \u00d7 Alb-Cre), respectively. A Lieber-DeCarli feeding model was used to induce glucose intolerance and insulin resistance in mice. Glucose tolerance test, insulin tolerance test, and insulin signaling experiments were performed to examine systemic and tissue-specific insulin sensitivity. We found that alcohol-fed hepatocyte TLR4 deficient mice (Tlr4LKO) had lower blood glucose levels in response to intraperitoneal injection of insulin. Moreover, increased phosphorylation of glycogen synthase kinase-3\u03b2 (GSK3\u03b2) was observed in the liver of Tlr4LKO mice after chronic alcohol intake. In contrast, when hepatic TLR4 was reactivated in mice (Tlr4LoxTB \u00d7 Alb-Cre), alcohol feeding caused glucose intolerance in these mice compared with littermate controls (Tlr4LoxTB). In addition, AKT phosphorylation was dramatically reduced in the liver and epididymal white adipose tissue (eWAT) of alcohol-fed Tlr4LoxTB \u00d7 Alb-Cre mice, which was similar to that of mice with whole-body TLR4 reactivation (Tlr4LoxTB \u00d7 Zp3-Cre). Collectively, these findings suggest that hepatocyte TLR4 is both required and sufficient in the development of insulin resistance induced by alcohol overconsumption.<\/jats:p>","DOI":"10.3390\/biom13030454","type":"journal-article","created":{"date-parts":[[2023,3,2]],"date-time":"2023-03-02T03:06:43Z","timestamp":1677726403000},"page":"454","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Hepatocyte Toll-Like Receptor 4 Mediates Alcohol-Induced Insulin Resistance in Mice"],"prefix":"10.3390","volume":"13","author":[{"given":"Piumi B.","family":"Wickramasinghe","sequence":"first","affiliation":[{"name":"Department of Biological Sciences, The University of Texas at Dallas, Richardson, TX 75080, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shuwen","family":"Qian","sequence":"additional","affiliation":[{"name":"Center for Hypothalamic Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lyndsey E.","family":"Langley","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, The University of Texas at Dallas, Richardson, TX 75080, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5922-0951","authenticated-orcid":false,"given":"Chen","family":"Liu","sequence":"additional","affiliation":[{"name":"Center for Hypothalamic Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7653-7395","authenticated-orcid":false,"given":"Lin","family":"Jia","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, The University of Texas at Dallas, Richardson, TX 75080, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"509","DOI":"10.2337\/diacare.19.5.509","article-title":"Alcohol and the NIDDM patient","volume":"19","author":"Bell","year":"1996","journal-title":"Diabetes Care"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1016\/j.alcohol.2009.10.005","article-title":"Alcohol consumption and higher incidence of impaired fasting glucose or type 2 diabetes in obese Korean men","volume":"43","author":"Roh","year":"2009","journal-title":"Alcohol"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1002\/hep.1840180115","article-title":"Normal splanchnic but impaired peripheral insulin-stimulated glucose uptake in cirrhosis","volume":"18","author":"Shmueli","year":"1993","journal-title":"Hepatology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"G515","DOI":"10.1152\/ajpgi.00455.2011","article-title":"Imipramine blocks ethanol-induced ASMase activation, ceramide generation, and PP2A activation, and ameliorates hepatic steatosis in ethanol-fed mice","volume":"302","author":"Liangpunsakul","year":"2012","journal-title":"Am. 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