PMID- 26928949
OWN - NLM
STAT- MEDLINE
DCOM- 20170724
LR  - 20180118
IS  - 1527-3350 (Electronic)
IS  - 0270-9139 (Linking)
VI  - 64
IP  - 1
DP  - 2016 Jul
TI  - Hyperhomocysteinemia activates the aryl hydrocarbon receptor/CD36 pathway to 
      promote hepatic steatosis in mice.
PG  - 92-105
LID - 10.1002/hep.28518 [doi]
AB  - 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. CONCLUSION: HHcy activates the AHR-CD36 pathway by 
      increasing hepatic LXA4 content, which results in hepatic steatosis. (Hepatology 
      2016;64:92-105).
CI  - (c) 2016 by the American Association for the Study of Liver Diseases.
FAU - Yao, Liu
AU  - Yao L
AD  - Collaborative Innovation Center of Tianjin for Medical Epigenetics and Department 
      of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China.
FAU - Wang, Chunjiong
AU  - Wang C
AD  - Collaborative Innovation Center of Tianjin for Medical Epigenetics and Department 
      of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China.
FAU - Zhang, Xu
AU  - Zhang X
AD  - Collaborative Innovation Center of Tianjin for Medical Epigenetics and Department 
      of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China.
FAU - Peng, Liyuan
AU  - Peng L
AD  - Collaborative Innovation Center of Tianjin for Medical Epigenetics and Department 
      of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China.
FAU - Liu, Wenli
AU  - Liu W
AD  - Collaborative Innovation Center of Tianjin for Medical Epigenetics and Department 
      of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China.
FAU - Zhang, Xuejiao
AU  - Zhang X
AD  - Collaborative Innovation Center of Tianjin for Medical Epigenetics and Department 
      of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China.
FAU - Liu, Yajin
AU  - Liu Y
AD  - Collaborative Innovation Center of Tianjin for Medical Epigenetics and Department 
      of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China.
FAU - He, Jinlong
AU  - He J
AD  - Collaborative Innovation Center of Tianjin for Medical Epigenetics and Department 
      of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China.
FAU - Jiang, Changtao
AU  - Jiang C
AD  - Department of Physiology and Pathophysiology, Peking University Health Science 
      Center, Beijing, China.
FAU - Ai, Ding
AU  - Ai D
AD  - Collaborative Innovation Center of Tianjin for Medical Epigenetics and Department 
      of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China.
FAU - Zhu, Yi
AU  - Zhu Y
AD  - Collaborative Innovation Center of Tianjin for Medical Epigenetics and Department 
      of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20160405
PL  - United States
TA  - Hepatology
JT  - Hepatology (Baltimore, Md.)
JID - 8302946
RN  - 0 (CD36 Antigens)
RN  - 0 (Lipoxins)
RN  - 0 (Receptors, Aryl Hydrocarbon)
RN  - 0 (lipoxin A4)
RN  - AE28F7PNPL (Methionine)
SB  - IM
MH  - Animals
MH  - CD36 Antigens/*metabolism
MH  - Fatty Liver/*metabolism
MH  - Hepatocytes/metabolism
MH  - Hyperhomocysteinemia/*metabolism
MH  - *Lipid Metabolism
MH  - Lipoxins/metabolism
MH  - Liver/metabolism
MH  - Male
MH  - Methionine
MH  - Mice, Inbred C57BL
MH  - Receptors, Aryl Hydrocarbon/*metabolism
EDAT- 2016/03/02 06:00
MHDA- 2017/07/25 06:00
CRDT- 2016/03/02 06:00
PHST- 2015/10/21 00:00 [received]
PHST- 2016/02/20 00:00 [accepted]
PHST- 2016/03/02 06:00 [entrez]
PHST- 2016/03/02 06:00 [pubmed]
PHST- 2017/07/25 06:00 [medline]
AID - 10.1002/hep.28518 [doi]
PST - ppublish
SO  - Hepatology. 2016 Jul;64(1):92-105. doi: 10.1002/hep.28518. Epub 2016 Apr 5.