title: Hyperhomocysteinemia activates the aryl hydrocarbon receptor/CD36 pathway to promote hepatic steatosis in mice.
abstract: 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-induced hepatic steatosis (HS). C57BL/6 mice were fed a high-methionine 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-regulated 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 A4 (LXA4 ), a metabolite of arachidonic acid, in HMD-fed mice. Furthermore, overexpression of 15-oxoprostaglandin 13-reductase 1, a LXA4 inactivation enzyme, inhibited Hcy-induced AHR activation, lipid uptake, and lipid accumulation. Moreover, LXA4 -induced up-regulation of CD36 and lipid uptake was inhibited by AHR siRNA in vitro in hepatocytes. Finally, treatment with an AHR antagonist reversed HHcy-induced lipid accumulation by inhibiting the AHR-CD36 pathway in mice.
  
  
  
  HHcy activates the AHR-CD36 pathway by increasing hepatic LXA4 content, which results in hepatic steatosis. (Hepatology 2016;64:92-105).
authors.affiliation: Collaborative Innovation Center of Tianjin for Medical Epigenetics and Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China.
authors.forename: Liu
authors.initials: L
authors.lastname: Yao
authors.affiliation: Collaborative Innovation Center of Tianjin for Medical Epigenetics and Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China.
authors.forename: Chunjiong
authors.initials: C
authors.lastname: Wang
authors.affiliation: Collaborative Innovation Center of Tianjin for Medical Epigenetics and Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China.
authors.forename: Xu
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Collaborative Innovation Center of Tianjin for Medical Epigenetics and Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China.
authors.forename: Liyuan
authors.initials: L
authors.lastname: Peng
authors.affiliation: Collaborative Innovation Center of Tianjin for Medical Epigenetics and Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China.
authors.forename: Wenli
authors.initials: W
authors.lastname: Liu
authors.affiliation: Collaborative Innovation Center of Tianjin for Medical Epigenetics and Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China.
authors.forename: Xuejiao
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Collaborative Innovation Center of Tianjin for Medical Epigenetics and Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China.
authors.forename: Yajin
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Collaborative Innovation Center of Tianjin for Medical Epigenetics and Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China.
authors.forename: Jinlong
authors.initials: J
authors.lastname: He
authors.affiliation: Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing, China.
authors.forename: Changtao
authors.initials: C
authors.lastname: Jiang
authors.affiliation: Collaborative Innovation Center of Tianjin for Medical Epigenetics and Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China.
authors.forename: Ding
authors.initials: D
authors.lastname: Ai
authors.affiliation: Collaborative Innovation Center of Tianjin for Medical Epigenetics and Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhu
mesh_terms: D000818:Animals; D018955:CD36 Antigens / Q000378:metabolism*; D005234:Fatty Liver / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism; D020138:Hyperhomocysteinemia / Q000378:metabolism*; D050356:Lipid Metabolism; D044045:Lipoxins / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D008715:Methionine; D008810:Mice, Inbred C57BL; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism*
chemical_list: D018955:CD36 Antigens; D044045:Lipoxins; D018336:Receptors, Aryl Hydrocarbon; C040527:lipoxin A4; D008715:Methionine