PMID- 32736671
OWN - NLM
STAT- MEDLINE
DCOM- 20210222
LR  - 20210222
IS  - 1090-2104 (Electronic)
IS  - 0006-291X (Linking)
VI  - 529
IP  - 3
DP  - 2020 Aug 27
TI  - Macrophage Lxralpha reduces atherosclerosis in Ldlr(-/-) mice independent of Arl7 
      transactivation.
PG  - 540-547
LID - S0006-291X(20)31288-2 [pii]
LID - 10.1016/j.bbrc.2020.06.071 [doi]
AB  - BACKGROUND: Liver X receptor alpha (Lxralpha) is a sterol-regulated transcription 
      factor that limits atherogenesis by regulating cholesterol homeostasis and 
      inflammation in macrophages. Transcriptional profiling identified the reverse 
      cholesterol transport protein Arf-like 7 (Arl7, Arl4c) as a Lxralpha target gene. We 
      hypothesized that the LXR response element (LXRE) sequence on the murine 
      macrophage Arl7 promoter may play a critical role in Lxralpha's atherosuppressive 
      effects. METHODS: Employing low density lipoprotein receptor-deficient mice with 
      macrophage-specific Lxralpha overexpression (Ldlr(-/-) MPhi-Lxralpha), we constructed a 
      novel in vivo Ldlr(-/-) MPhi-Lxralpha Arl7(MutLXRE) model possessing 
      macrophage-specific mutations within the Arl7 promoter LXRE sequences 
      (Arl7(MutLXRE)) using the CRISPR/spCas9 genome editing technique. In vitro and 
      in vivo transplantation studies were conducted using bone marrow-derived 
      macrophages (BMDMs) and peritoneal macrophages (PMs). RESULTS: Ldlr(-/-), 
      Ldlr(-/-) MPhi-Lxralpha, and Ldlr(-/-) MPhi-Lxralpha Arl7(MutLXRE) mice on a 60% high-fat 
      diet displayed no significant differences in body weight, fat mass, glucose 
      homeostasis, or lipid metabolism. Macrophage Lxralpha promoted Arl7 expression, 
      enhanced cholesterol efflux, and reduced foam cell formation in an Arl7 
      LXRE-dependent manner. In contrast, Lxralpha reduced macrophage activation, 
      inflammatory cytokine expression, and efferocytosis independent of Arl7 LXRE. 
      Western diet-fed Ldlr(-/-) mice reconstituted with transgenic BMDMs revealed that 
      macrophage Lxralpha reduced atherosclerotic plaque formation independent of Arl7 
      LXRE. CONCLUSION: Lxralpha's anti-atherosclerotic effects in Ldlr(-/-) mice are not 
      primarily attributable to Lxralpha's influence on Arl7 expression. This evidence 
      suggests that Lxralpha's effects on plaque inflammation may be more critical to 
      in vivo atherogenesis than its effects on macrophage cholesterol efflux and foam 
      cell development.
CI  - Copyright (c) 2020 Elsevier Inc. All rights reserved.
FAU - Yin, Yongjun
AU  - Yin Y
AD  - Department of Cardiology, Affiliated Hospital of Chengdu University of 
      Traditional Chinese Medicine, Chengdu, Sichuan, China.
FAU - Zeng, Silu
AU  - Zeng S
AD  - Department of Cardiology, Affiliated Hospital of Chengdu University of 
      Traditional Chinese Medicine, Chengdu, Sichuan, China.
FAU - Li, Yanwei
AU  - Li Y
AD  - Department of Cardiology, Affiliated Hospital of Chengdu University of 
      Traditional Chinese Medicine, Chengdu, Sichuan, China.
FAU - Wu, Zhou
AU  - Wu Z
AD  - Department of Cardiology, Affiliated Hospital of Chengdu University of 
      Traditional Chinese Medicine, Chengdu, Sichuan, China.
FAU - Huang, Dajun
AU  - Huang D
AD  - Department of Cardiology, Affiliated Hospital of Chengdu University of 
      Traditional Chinese Medicine, Chengdu, Sichuan, China.
FAU - Gao, Peiyang
AU  - Gao P
AD  - Department of Cardiology, Affiliated Hospital of Chengdu University of 
      Traditional Chinese Medicine, Chengdu, Sichuan, China. Electronic address: 
      y18980687436@163.com.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200715
PL  - United States
TA  - Biochem Biophys Res Commun
JT  - Biochemical and biophysical research communications
JID - 0372516
RN  - 0 (Arl4c protein, mouse)
RN  - 0 (Liver X Receptors)
RN  - 0 (NR1H3 protein, human)
RN  - 0 (Receptors, LDL)
RN  - 97C5T2UQ7J (Cholesterol)
RN  - EC 3.6.5.2 (ADP-Ribosylation Factors)
SB  - IM
MH  - ADP-Ribosylation Factors/genetics/*metabolism
MH  - Animals
MH  - Atherosclerosis/genetics/*metabolism/therapy
MH  - Cholesterol/metabolism
MH  - Foam Cells/metabolism
MH  - Lipid Metabolism/genetics
MH  - Liver X Receptors/*metabolism
MH  - Macrophages/*metabolism/transplantation
MH  - Macrophages, Peritoneal/*metabolism/transplantation
MH  - Male
MH  - Mice, Knockout
MH  - Mice, Transgenic
MH  - Plaque, Atherosclerotic/genetics/metabolism/therapy
MH  - Receptors, LDL/genetics/*metabolism
MH  - Transcriptional Activation
OTO - NOTNLM
OT  - ARL4C
OT  - ARL7
OT  - Atherosclerosis
OT  - LXR
OT  - Macrophage
COIS- Declaration of competing interest The authors declare that they have no known 
      competing interests or personal relationships that could have appeared to 
      influence the work reported in this paper.
EDAT- 2020/08/02 06:00
MHDA- 2021/02/23 06:00
CRDT- 2020/08/02 06:00
PHST- 2020/06/10 00:00 [received]
PHST- 2020/06/15 00:00 [accepted]
PHST- 2020/08/02 06:00 [entrez]
PHST- 2020/08/02 06:00 [pubmed]
PHST- 2021/02/23 06:00 [medline]
AID - S0006-291X(20)31288-2 [pii]
AID - 10.1016/j.bbrc.2020.06.071 [doi]
PST - ppublish
SO  - Biochem Biophys Res Commun. 2020 Aug 27;529(3):540-547. doi: 
      10.1016/j.bbrc.2020.06.071. Epub 2020 Jul 15.