PMID- 31662443
OWN - NLM
STAT- MEDLINE
DCOM- 20200710
LR  - 20210217
IS  - 1539-7262 (Electronic)
IS  - 0022-2275 (Print)
IS  - 0022-2275 (Linking)
VI  - 60
IP  - 12
DP  - 2019 Dec
TI  - CXCL12 promotes atherosclerosis by downregulating ABCA1 expression via the 
      CXCR4/GSK3beta/beta-catenin(T120)/TCF21 pathway.
PG  - 2020-2033
LID - 10.1194/jlr.RA119000100 [doi]
AB  - CXC chemokine ligand 12 (CXCL12) is a member of the CXC chemokine family and 
      mainly acts on cell chemotaxis. CXCL12 also elicits a proatherogenic role, but 
      the molecular mechanisms have not been fully defined yet. We aimed to reveal if 
      and how CXCL12 promoted atherosclerosis via regulating lipid metabolism. In 
      vitro, our data showed that CXCL12 could reduce ABCA1 expression, and it mediated 
      cholesterol efflux from THP-1-derived macrophages to apoA-I. Data from the 
      luciferase reporter gene and chromatin immunoprecipitation assays revealed that 
      transcription factor 21 (TCF21) stimulated the transcription of ABCA1 via binding 
      to its promoter region, which was repressed by CXCL12. We found that CXCL12 
      increased the levels of phosphorylated glycogen synthase kinase 3beta (GSK3beta) and 
      the phosphorylation of beta-catenin at the Thr120 position. Inactivation of GSK3beta or 
      beta-catenin increased the expression of TCF21 and ABCA1. Further, knockdown or 
      inhibition of CXC chemokine receptor 4 (CXCR4) blocked the effects of CXCL12 on 
      TCF21 and ABCA1 expression and the phosphorylation of GSK3beta and beta-catenin. In 
      vivo, the overexpression of CXCL12 in Apoe(-/-) mice via lentivirus enlarged the 
      atherosclerotic lesion area and increased macrophage infiltration in 
      atherosclerotic plaques. We further found that the overexpression of CXCL12 
      reduced the efficiency of reverse cholesterol transport and plasma HDL-C levels, 
      decreased ABCA1 expression in the aorta and mouse peritoneal macrophages (MPMs), 
      and suppressed cholesterol efflux from MPMs to apoA-I in Apoe(-/-) mice. 
      Collectively, these findings suggest that CXCL12 interacts with CXCR4 and then 
      activates the GSK-3beta/beta-catenin(T120)/TCF21 signaling pathway to inhibit 
      ABCA1-dependent cholesterol efflux from macrophages and aggravate 
      atherosclerosis. Targeting CXCL12 may be a novel and promising strategy for the 
      prevention and treatment of atherosclerotic cardiovascular diseases.
CI  - Copyright (c) 2019 Gao et al.
FAU - Gao, Jia-Hui
AU  - Gao JH
AUID- ORCID: 0000-0002-7459-4361
AD  - Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of 
      Hunan Province, Hunan International Scientific and Technological Cooperation Base 
      of Arteriosclerotic Disease, Medical Research Experiment Center, Hunan Province 
      Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang 
      Medical College, University of South China, Hengyang, Hunan, China.
FAU - He, Lin-Hao
AU  - He LH
AD  - School of Pharmacy and Life Science College, Hunan Province Cooperative 
      Innovation Center for Molecular Target New Drug Study, Hengyang Medical College, 
      University of South China, Hengyang, Hunan, China.
FAU - Yu, Xiao-Hua
AU  - Yu XH
AD  - Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of 
      Hunan Province, Hunan International Scientific and Technological Cooperation Base 
      of Arteriosclerotic Disease, Medical Research Experiment Center, Hunan Province 
      Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang 
      Medical College, University of South China, Hengyang, Hunan, China.
FAU - Zhao, Zhen-Wang
AU  - Zhao ZW
AD  - Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of 
      Hunan Province, Hunan International Scientific and Technological Cooperation Base 
      of Arteriosclerotic Disease, Medical Research Experiment Center, Hunan Province 
      Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang 
      Medical College, University of South China, Hengyang, Hunan, China.
FAU - Wang, Gang
AU  - Wang G
AD  - Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of 
      Hunan Province, Hunan International Scientific and Technological Cooperation Base 
      of Arteriosclerotic Disease, Medical Research Experiment Center, Hunan Province 
      Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang 
      Medical College, University of South China, Hengyang, Hunan, China.
FAU - Zou, Jin
AU  - Zou J
AD  - Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of 
      Hunan Province, Hunan International Scientific and Technological Cooperation Base 
      of Arteriosclerotic Disease, Medical Research Experiment Center, Hunan Province 
      Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang 
      Medical College, University of South China, Hengyang, Hunan, China.
FAU - Wen, Feng-Jiao
AU  - Wen FJ
AD  - School of Pharmacy and Life Science College, Hunan Province Cooperative 
      Innovation Center for Molecular Target New Drug Study, Hengyang Medical College, 
      University of South China, Hengyang, Hunan, China.
FAU - Zhou, Li
AU  - Zhou L
AD  - Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of 
      Hunan Province, Hunan International Scientific and Technological Cooperation Base 
      of Arteriosclerotic Disease, Medical Research Experiment Center, Hunan Province 
      Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang 
      Medical College, University of South China, Hengyang, Hunan, China.
FAU - Wan, Xiang-Jun
AU  - Wan XJ
AD  - Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of 
      Hunan Province, Hunan International Scientific and Technological Cooperation Base 
      of Arteriosclerotic Disease, Medical Research Experiment Center, Hunan Province 
      Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang 
      Medical College, University of South China, Hengyang, Hunan, China.
FAU - Zhang, Da-Wei
AU  - Zhang DW
AD  - Department of Pediatrics and Group on the Molecular and Cell Biology of Lipids, 
      University of Alberta, Edmonton, Alberta, Canada.
FAU - Tang, Chao-Ke
AU  - Tang CK
AD  - Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of 
      Hunan Province, Hunan International Scientific and Technological Cooperation Base 
      of Arteriosclerotic Disease, Medical Research Experiment Center, Hunan Province 
      Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang 
      Medical College, University of South China, Hengyang, Hunan, China 
      tangchaoke@qq.com.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20191029
PL  - United States
TA  - J Lipid Res
JT  - Journal of lipid research
JID - 0376606
RN  - 0 (ATP Binding Cassette Transporter 1)
RN  - 0 (Apolipoproteins E)
RN  - 0 (Basic Helix-Loop-Helix Transcription Factors)
RN  - 0 (CXCR4 protein, human)
RN  - 0 (Chemokine CXCL12)
RN  - 0 (Receptors, CXCR4)
RN  - 0 (TCF21 protein, human)
RN  - 0 (beta Catenin)
RN  - 97C5T2UQ7J (Cholesterol)
RN  - EC 2.7.11.1 (Glycogen Synthase Kinase 3 beta)
SB  - IM
MH  - ATP Binding Cassette Transporter 1/*genetics
MH  - Animals
MH  - Apolipoproteins E/deficiency
MH  - Atherosclerosis/genetics/*metabolism/pathology
MH  - Basic Helix-Loop-Helix Transcription Factors/*metabolism
MH  - Chemokine CXCL12/*metabolism
MH  - Cholesterol/metabolism
MH  - Down-Regulation
MH  - Glycogen Synthase Kinase 3 beta/*metabolism
MH  - HEK293 Cells
MH  - Humans
MH  - Macrophages/metabolism
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Receptors, CXCR4/*metabolism
MH  - beta Catenin/*metabolism
PMC - PMC6889714
OTO - NOTNLM
OT  - ATP binding cassette transporter A1
OT  - CXC chemokine ligand 12
OT  - CXC chemokine receptor 4
OT  - cholesterol efflux
OT  - glycogen synthase kinase 3beta
OT  - transcription factor 21
COIS- The authors declare that they have no conflicts of interest with the contents of 
      this article.
EDAT- 2019/10/31 06:00
MHDA- 2020/07/11 06:00
PMCR- 2020/12/01
CRDT- 2019/10/31 06:00
PHST- 2019/04/30 00:00 [received]
PHST- 2019/10/22 00:00 [revised]
PHST- 2019/10/31 06:00 [pubmed]
PHST- 2020/07/11 06:00 [medline]
PHST- 2019/10/31 06:00 [entrez]
PHST- 2020/12/01 00:00 [pmc-release]
AID - S0022-2275(20)31041-5 [pii]
AID - rA119000100 [pii]
AID - 10.1194/jlr.RA119000100 [doi]
PST - ppublish
SO  - J Lipid Res. 2019 Dec;60(12):2020-2033. doi: 10.1194/jlr.RA119000100. Epub 2019 
      Oct 29.