PMID- 27365310
OWN - NLM
STAT- MEDLINE
DCOM- 20170601
LR  - 20220409
IS  - 0006-3002 (Print)
IS  - 0006-3002 (Linking)
VI  - 1861
IP  - 9 Pt A
DP  - 2016 Sep
TI  - MEK1/2 inhibitors activate macrophage ABCG1 expression and reverse cholesterol 
      transport-An anti-atherogenic function of ERK1/2 inhibition.
PG  - 1180-1191
LID - S1388-1981(16)30169-X [pii]
LID - 10.1016/j.bbalip.2016.06.017 [doi]
AB  - Expression of ATP-binding cassette transporter G1 (ABCG1), a molecule 
      facilitating cholesterol efflux to HDL, is activated by liver X receptor (LXR). 
      In this study, we investigated if inhibition of ERK1/2 can activate macrophage 
      ABCG1 expression and functions. MEK1/2 inhibitors, PD98059 and U0126, increased 
      ABCG1 mRNA and protein expression, and activated the natural ABCG1 promoter but 
      not the promoter with the LXR responsive element (LXRE) deletion. Inhibition of 
      ABCG1 expression by ABCG1 siRNA did enhance the formation of macrophage/foam 
      cells and it attenuated the inhibitory effect of MEK1/2 inhibitors on foam cell 
      formation. MEK1/2 inhibitors activated macrophage cholesterol efflux to HDL in 
      vitro, and they enhanced reverse cholesterol transport (RCT) in vivo. ApoE 
      deficient (apoE(-/-)) mice receiving U0126 treatment had reduced sinus lesions in 
      the aortic root which was associated with activated macrophage ABCG1 expression 
      in the lesion areas. MEK1/2 inhibitors coordinated the RXR agonist, but not the 
      LXR agonist, to induce ABCG1 expression. Furthermore, induction of ABCG1 
      expression by MEK1/2 inhibitors was associated with activation of SIRT1, a 
      positive regulator of LXR activity, and inactivation of SULT2B1 and RIP140, two 
      negative regulators of LXR activity. Taken together, our study suggests that 
      MEK1/2 inhibitors activate macrophage ABCG1 expression/RCT, and inhibit foam cell 
      formation and lesion development by multiple mechanisms, supporting the concept 
      that ERK1/2 inhibition is anti-atherogenic.
CI  - Copyright (c) 2016 Elsevier B.V. All rights reserved.
FAU - Zhang, Ling
AU  - Zhang L
AD  - Department of Cardiology, Xijing Hospital, the 4th Military Medical University, 
      Xi'an, China.
FAU - Chen, Yuanli
AU  - Chen Y
AD  - College of Biomedical Engineering, Hefei University of Technology, Hefei, China; 
      School of Medicine, Nankai University, Tianjin, China.
FAU - Yang, Xiaoxiao
AU  - Yang X
AD  - College of Life Sciences, Nankai University, Tianjin, China.
FAU - Yang, Jie
AU  - Yang J
AD  - College of Life Sciences, Nankai University, Tianjin, China.
FAU - Cao, Xingyue
AU  - Cao X
AD  - College of Life Sciences, Nankai University, Tianjin, China.
FAU - Li, Xiaoju
AU  - Li X
AD  - College of Life Sciences, Nankai University, Tianjin, China.
FAU - Li, Luyuan
AU  - Li L
AD  - College of Pharmacy, Nankai University, Tianjin, China.
FAU - Miao, Qing Robert
AU  - Miao QR
AD  - Medical College of Wisconsin, Milwaukee, USA.
FAU - Hajjar, David P
AU  - Hajjar DP
AD  - Weill Cornell Medical College, New York, USA.
FAU - Duan, Yajun
AU  - Duan Y
AD  - College of Biomedical Engineering, Hefei University of Technology, Hefei, China; 
      College of Life Sciences, Nankai University, Tianjin, China; State Key Laboratory 
      of Medicinal Chemical Biology, Collaborative Innovation Center of Biotherapy, 
      Nankai University, Tianjin, China. Electronic address: yduan@hfut.edu.cn.
FAU - Han, Jihong
AU  - Han J
AD  - College of Biomedical Engineering, Hefei University of Technology, Hefei, China; 
      College of Life Sciences, Nankai University, Tianjin, China; State Key Laboratory 
      of Medicinal Chemical Biology, Collaborative Innovation Center of Biotherapy, 
      Nankai University, Tianjin, China. Electronic address: hanjihong2015@hfut.edu.cn.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20160627
PL  - Netherlands
TA  - Biochim Biophys Acta
JT  - Biochimica et biophysica acta
JID - 0217513
RN  - 0 (ABCG1 protein, mouse)
RN  - 0 (ATP Binding Cassette Transporter, Subfamily G, Member 1)
RN  - 0 (Apolipoproteins E)
RN  - 0 (Butadienes)
RN  - 0 (Flavonoids)
RN  - 0 (Liver X Receptors)
RN  - 0 (Nitriles)
RN  - 0 (Retinoid X Receptor alpha)
RN  - 0 (U 0126)
RN  - 97C5T2UQ7J (Cholesterol)
RN  - EC 2.7.12.2 (MAP Kinase Kinase 1)
RN  - EC 2.7.12.2 (Map2k1 protein, mouse)
RN  - EC 3.5.1.- (Sirt1 protein, mouse)
RN  - EC 3.5.1.- (Sirtuin 1)
RN  - SJE1IO5E3I (2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one)
SB  - IM
MH  - ATP Binding Cassette Transporter, Subfamily G, Member 1/*biosynthesis/genetics
MH  - Animals
MH  - Aorta/metabolism
MH  - Apolipoproteins E/genetics
MH  - Atherosclerosis/drug therapy/*genetics/metabolism
MH  - Biological Transport/drug effects/*genetics
MH  - Butadienes/administration & dosage
MH  - Cholesterol/genetics/*metabolism
MH  - Flavonoids/administration & dosage
MH  - Foam Cells/drug effects/metabolism
MH  - Gene Expression Regulation/drug effects
MH  - Humans
MH  - Liver X Receptors/biosynthesis/*genetics
MH  - MAP Kinase Kinase 1/antagonists & inhibitors/metabolism
MH  - MAP Kinase Signaling System/drug effects
MH  - Macrophages/drug effects/metabolism
MH  - Mice
MH  - Mice, Knockout
MH  - Nitriles/administration & dosage
MH  - Promoter Regions, Genetic
MH  - Retinoid X Receptor alpha/agonists/genetics
MH  - Sirtuin 1/biosynthesis
OTO - NOTNLM
OT  - ABCG1
OT  - Atherosclerosis
OT  - LXR
OT  - MEK1/2
OT  - RCT
OT  - SIRT1
EDAT- 2016/07/02 06:00
MHDA- 2017/06/02 06:00
CRDT- 2016/07/02 06:00
PHST- 2016/02/29 00:00 [received]
PHST- 2016/06/03 00:00 [revised]
PHST- 2016/06/24 00:00 [accepted]
PHST- 2016/07/02 06:00 [entrez]
PHST- 2016/07/02 06:00 [pubmed]
PHST- 2017/06/02 06:00 [medline]
AID - S1388-1981(16)30169-X [pii]
AID - 10.1016/j.bbalip.2016.06.017 [doi]
PST - ppublish
SO  - Biochim Biophys Acta. 2016 Sep;1861(9 Pt A):1180-1191. doi: 
      10.1016/j.bbalip.2016.06.017. Epub 2016 Jun 27.