{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T18:56:51Z","timestamp":1790535411337,"version":"4.1.0"},"reference-count":37,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2018,4,19]],"date-time":"2018-04-19T00:00:00Z","timestamp":1524096000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH-NIAAA","award":["R01 AA017442"],"award-info":[{"award-number":["R01 AA017442"]}]},{"name":"Nature Science Foundation of China","award":["81102111"],"award-info":[{"award-number":["81102111"]}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J Cellular Molecular Medi"],"published-print":{"date-parts":[[2018,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Lipotoxicity induced by saturated fatty acids (<jats:styled-content style=\"fixed-case\">SFA<\/jats:styled-content>s) plays a pathological role in the development of non\u2010alcoholic fatty liver disease (<jats:styled-content style=\"fixed-case\">NAFLD<\/jats:styled-content>); however, the exact mechanism(s) remain to be clearly elucidated. Toll\u2010like receptor (<jats:styled-content style=\"fixed-case\">TLR<\/jats:styled-content>) 4 plays a fundamental role in activating the innate immune system. Intriguingly, hepatocytes express <jats:styled-content style=\"fixed-case\">TLR<\/jats:styled-content>4 and machinery for <jats:styled-content style=\"fixed-case\">TLR<\/jats:styled-content>4 signalling pathway. That liver\u2010specific <jats:styled-content style=\"fixed-case\">TLR<\/jats:styled-content>4 knockout mice are protective against diet\u2010induced <jats:styled-content style=\"fixed-case\">NAFLD<\/jats:styled-content> suggests that hepatocyte <jats:styled-content style=\"fixed-case\">TLR<\/jats:styled-content>4 signalling pathway plays an important role in <jats:styled-content style=\"fixed-case\">NAFLD<\/jats:styled-content> pathogenesis. Herein, using cultured hepatocytes, we sought to directly examine the role of <jats:styled-content style=\"fixed-case\">TLR<\/jats:styled-content>4 signalling pathway in palmitate\u2010elicited hepatotoxicity and to elucidate underlying mechanism(s). Our data reveal that palmitate exposure up\u2010regulates <jats:styled-content style=\"fixed-case\">TLR<\/jats:styled-content>4 expression at both <jats:styled-content style=\"fixed-case\">mRNA<\/jats:styled-content> and protein levels in hepatocytes, which are associated with <jats:styled-content style=\"fixed-case\">NF<\/jats:styled-content>\u2010\u03baB activation. The inhibition of <jats:styled-content style=\"fixed-case\">TLR<\/jats:styled-content>4 signalling pathway through both pharmacological and genetic approaches abolished palmitate\u2010induced cell death, suggesting that <jats:styled-content style=\"fixed-case\">TLR<\/jats:styled-content>4 signalling pathway activation contributes to palmitate\u2010induced hepatotoxicity. Mechanistic investigations demonstrate that inositol\u2010requiring enzyme 1\u03b1 (<jats:styled-content style=\"fixed-case\">IRE<\/jats:styled-content>1\u03b1), one of three major signal transduction pathways activated during endoplasmic reticulum (<jats:styled-content style=\"fixed-case\">ER<\/jats:styled-content>) stress, is the downstream target of palmitate\u2010elicited <jats:styled-content style=\"fixed-case\">TLR<\/jats:styled-content>4 activation and mechanistically implicated in <jats:styled-content style=\"fixed-case\">TLR<\/jats:styled-content>4 activation\u2010triggered cell death in response to palmitate exposure. Collectively, our data identify that the <jats:styled-content style=\"fixed-case\">TLR<\/jats:styled-content>4\u2010<jats:styled-content style=\"fixed-case\">IRE<\/jats:styled-content>1\u03b1 pathway activation contributes to palmitate\u2010elicited lipotoxicity in hepatocytes. Our findings suggest that targeting <jats:styled-content style=\"fixed-case\">TLR<\/jats:styled-content>4\u2010<jats:styled-content style=\"fixed-case\">IRE<\/jats:styled-content>1\u03b1 pathway can be a potential therapeutic choice for the treatment of <jats:styled-content style=\"fixed-case\">NAFLD<\/jats:styled-content> as well as other metabolic disorders, with lipotoxicity being the principal pathomechanism.<\/jats:p>","DOI":"10.1111\/jcmm.13636","type":"journal-article","created":{"date-parts":[[2018,4,19]],"date-time":"2018-04-19T17:50:20Z","timestamp":1524160220000},"page":"3572-3581","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["The <scp>TLR<\/scp>4\u2010<scp>IRE<\/scp>1\u03b1 pathway activation contributes to palmitate\u2010elicited lipotoxicity in hepatocytes"],"prefix":"10.1111","volume":"22","author":[{"given":"Chen","family":"Shen","sequence":"first","affiliation":[{"name":"Department of 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