{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T14:33:13Z","timestamp":1783607593913,"version":"3.55.0"},"reference-count":44,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2016,7]]},"abstract":"<jats:p>Hyperhomocysteinemia (HHcy) is associated with liver diseases such as fatty liver and hepatic fibrosis; however, the underlying mechanism is still largely unknown. The current study aimed to explore the signaling pathway involved in HHcy\u2010induced hepatic steatosis (HS). C57BL\/6 mice were fed a high\u2010methionine diet (HMD) for 4 and 8 weeks to establish the HHcy mouse model. Compared to a chow diet, the HMD induced hepatic steatosis and elevated hepatic expression of CD36, a fatty acid transport protein. The increased CD36 expression was associated with activation of the aryl hydrocarbon receptor (AHR). In primary cultured hepatocytes, high levels of homocysteine (Hcy) treatment up\u2010regulated CD36 and increased subsequent lipid uptake; both were significantly attenuated by small interfering RNA (siRNA) knockdown of CD36 and AHR. Chromatin immunoprecipitation assay revealed that Hcy promoted binding of AHR to the CD36 promoter, and transient transfection assay demonstrated markedly increased activity of the AHR response element by Hcy, which was ligand dependent. Mass spectrometry revealed significantly increased hepatic content of lipoxin A<jats:sub>4<\/jats:sub> (LXA<jats:sub>4<\/jats:sub>), a metabolite of arachidonic acid, in HMD\u2010fed mice. Furthermore, overexpression of 15\u2010oxoprostaglandin 13\u2010reductase 1, a LXA<jats:sub>4<\/jats:sub> inactivation enzyme, inhibited Hcy\u2010induced AHR activation, lipid uptake, and lipid accumulation. Moreover, LXA<jats:sub>4<\/jats:sub>\u2010induced up\u2010regulation of CD36 and lipid uptake was inhibited by AHR siRNA <jats:italic toggle=\"yes\">in vitro<\/jats:italic> in hepatocytes. Finally, treatment with an AHR antagonist reversed HHcy\u2010induced lipid accumulation by inhibiting the AHR\u2010CD36 pathway in mice. <jats:italic toggle=\"yes\">Conclusion:<\/jats:italic> HHcy activates the AHR\u2010CD36 pathway by increasing hepatic LXA<jats:sub>4<\/jats:sub> content, which results in hepatic steatosis. (H<jats:sc>epatology<\/jats:sc> 2016;64:92\u2010105)<\/jats:p>","DOI":"10.1002\/hep.28518","type":"journal-article","created":{"date-parts":[[2016,2,29]],"date-time":"2016-02-29T17:38:53Z","timestamp":1456767533000},"page":"92-105","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":84,"title":["Hyperhomocysteinemia activates the aryl hydrocarbon receptor\/CD36 pathway to promote hepatic steatosis in mice"],"prefix":"10.1097","volume":"64","author":[{"given":"Liu","family":"Yao","sequence":"first","affiliation":[{"name":"Collaborative Innovation Center of Tianjin for Medical Epigenetics and Department of Physiology and Pathophysiology,Tianjin Medical University,Tianjin,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunjiong","family":"Wang","sequence":"additional","affiliation":[{"name":"Collaborative Innovation Center of Tianjin for Medical Epigenetics and Department of Physiology and 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