{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,18]],"date-time":"2025-11-18T21:02:16Z","timestamp":1763499736563,"version":"3.40.5"},"reference-count":35,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2022,4,11]],"date-time":"2022-04-11T00:00:00Z","timestamp":1649635200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100004731","name":"Natural Science Foundation of Zhejiang Province","doi-asserted-by":"publisher","award":["LZ21H030001"],"award-info":[{"award-number":["LZ21H030001"]}],"id":[{"id":"10.13039\/501100004731","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81773981","81773422"],"award-info":[{"award-number":["81773981","81773422"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Alcoholism Clin &amp;amp; Exp Res"],"published-print":{"date-parts":[[2022,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background and aims<\/jats:title><jats:p>Excessive alcohol consumption predisposes drinkers to develop alcoholic cardiomyopathy. Although cardiomyocyte loss is the hallmark of cardiomyopathy, the underlying mechanism remains elusive. This study examined the potential mechanism of alcohol\u2010induced cardiomyocyte death in a mouse model of alcoholic cardiomyopathy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We established the alcoholic cardiomyopathy mouse model using C57BL\/6J mice and confirmed it via echocardiography and histological examination. The cardiac ceramide content and profile were analyzed with a triple\u2010quadrupole mass spectrometer. The molecular mechanism underlying the accumulation of ceramide due to chronic alcohol consumption and ceramide\u2010induced cardiomyocyte death were investigated by in vivo and in vitro models. Finally, we established a TLR4 mutation model to explore the function of TLR4 in CH3\/HeJ mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Cardiac lipotoxicity that followed alcohol exposure resulted mainly in C16:0\u2010, C18:0\u2010, and C24:1\u2010ceramide aggregation. Genes encoding the sphingosine hydrolysis enzymes (SMPD1 and SMPD2) rather than de novo synthetic biomarkers were markedly upregulated. Exogenous ceramide mimics (C6\u2010ceramide) werenderlying the accumulation of ceramide observed to cause H9C2 cardiomyocyte\u2010like cell death, which was consistent with results under palmate acid (PA) treatment. As a ceramide precursor, PA induces intracellular ceramide generation through TLR4 signaling, which can be abolished by an inhibitor of ceramide synthesis. Furthermore, mechanistic investigations demonstrated that pharmacological or genetic inhibition of TLR4 attenuated PA\u2010induced cell death and corresponding ceramide production. Moreover, global mutation of TLR4 in CH3\/HeJ mice significantly reduced the accumulation of C24:0, C24:1, OH_C24:1, and total ceramide following alcohol challenge.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our findings demonstrate that ceramide accumulation plays a crucial role in alcoholic cardiomyopathy, effects that are partially mediated through the TLR4\u2010dependent pathway.<\/jats:p><\/jats:sec>","DOI":"10.1111\/acer.14822","type":"journal-article","created":{"date-parts":[[2022,4,4]],"date-time":"2022-04-04T05:40:47Z","timestamp":1649050847000},"page":"1011-1022","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Ectopic accumulation of ceramide in cardiomyocytes modulates alcoholic cardiomyopathy via the TLR4\u2010dependent pathway"],"prefix":"10.1111","volume":"46","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0276-2538","authenticated-orcid":false,"given":"Cui","family":"Wang","sequence":"first","affiliation":[{"name":"School of Life Science Zhejiang Chinese Medical University  Hangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Songtao","family":"Li","sequence":"additional","affiliation":[{"name":"School of Public Health Zhejiang Chinese Medical University  Hangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qingsheng","family":"Liu","sequence":"additional","affiliation":[{"name":"Hangzhou TCM Hospital of Zhejiang Chinese Medical University (Hangzhou Hospital of Traditional Chinese Medicine)  Hangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qianyu","family":"Qian","sequence":"additional","affiliation":[{"name":"School of Life Science Zhejiang Chinese Medical University  Hangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ai","family":"Fu","sequence":"additional","affiliation":[{"name":"School of Life Science Zhejiang Chinese Medical University  Hangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lin","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Life Science Zhejiang Chinese Medical University  Hangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Jiaxing Dong Fang Guo Yao Prepared Decoction Pieces of Traditional Chinese Medicine Co., Ltd.  Jiaxing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Toshinobu","family":"Suzaki","sequence":"additional","affiliation":[{"name":"Graduate School of Science Kobe University  Kobe Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"ZhiLing","family":"Yu","sequence":"additional","affiliation":[{"name":"School of Chinese Medicine Hong Kong Baptist University  Hong Kong China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaobing","family":"Dou","sequence":"additional","affiliation":[{"name":"School of Life Science Zhejiang Chinese Medical University  Hangzhou 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