Beyond the Foam Cell: The Role of LXRs in Preventing Atherogenesis
Abstract
:1. Introduction
2. Pathogenesis of Atherosclerosis
2.1. Structure of the Aorta
2.2. Contributions of the Endothelium to Atherosclerosis
2.2.1. Endothelial Dysfunction
2.2.2. Endothelial Activation
2.3. Late Stages of Atherosclerosis
3. Liver X Receptors
3.1. LXRs Preserve Cholesterol Homeostasis
3.2. LXRs Repress Inflammation
4. LXRs and Atherosclerosis: A Macrophage Cholesterol Efflux-Centered Paradigm
5. LXRs and Hematopoietic Cell Types
5.1. Contributions of Hematopoietic Cell Types to Atherosclerosis
5.2. LXRs and Their Target Genes Regulate Hematopoietic Cell Types: Implications for Atherosclerosis
6. LXRs and Vascular Cell Types
6.1. Endothelial Cells
6.2. Smooth Muscle Cells
7. Emerging Mechanisms of LXRs in Atherosclerosis
8. Concluding Remarks
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
CVD | Cardiovascular disease |
LXR | Liver X receptor |
SREBP-1c | Sterol response element binding protein-1c |
ACC | Acetyl-CoA carboxylase |
FAS | Fatty acid synthase |
SCD-1 | Stearoyl-CoA desaturase-1 |
SMC | Smooth muscle cell |
eNOS | Endothelial nitric oxide synthase |
LDL | Low-density lipoprotein |
VLA-4 | Very late antigen-4 |
VCAM-1 | Vascular cell adhesion molecule-1 |
oxLDL | Oxidized low-density lipoprotein |
TNFα | Tumor necrosis factor α |
ICAM-1 | Intercellular adhesion molecule-1 |
NFκB | Nuclear factor κB |
M-CSF | Macrophage colony stimulating factor |
iNOS | Inducible nitric oxide synthase |
Il | Interleukin |
MMP | Matrix metalloprotease |
Apo | Apolipoprotein |
HDL | High-density lipoprotein |
Npc1l1 | Niemann-pick C1-like 1 |
MCP-1 | Monocyte chemoattractant protein-1 |
LDLR | Low-density lipoprotein receptor |
CCR7 | C-c chemokine receptor 7 |
HSC | Hematopoietic stem cell |
GM-CSF | Granulocyte-monocyte colony stimulating factor |
Nox2 | NADPH oxidase 2 |
G-CSF | Granulocyte colony stimulating factor |
VEGF | Vascular endothelial growth factor |
CD38 | Cluster of differentiation 38 |
KLF4 | Krüppel-like factor 4 |
S1PR2 | Sphingosine-1-phosphate receptor 2 |
LPS | Lipopolysaccharide |
LncRNA | Long non-coding RNA |
DDX17 | DEAD-box helicase 17 |
TTC39B | Tetratricopeptide repeat domain protein 39B |
WT | Wildtype |
WD | Western diet |
Tg | Transgenic |
MΦ | Macrophage |
T09 | T0901317 |
GW | GW3965 |
STZ | Streptozotocin |
BCA | Brachiocephalic artery |
BM | Bone marrow |
BMDM | Bone marrow-derived macrophages |
BMT | Bone marrow transplant |
OE | Overexpression |
RCT | Reverse cholesterol transport |
VLDL | Very low-density lipoprotein |
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Reference | Description of Study 2 | Major Findings | Conclusions | |
---|---|---|---|---|
Whole-body gain and loss-of-function studies | ||||
[148] | Chow-fed WT vs. Lxrαβ−/− at 18 months | ↑ lipid in aortic root of Lxrαβ−/− | LXRs regulate atherosclerotic development | |
[89] | WD-fed Apoe−/−, Ldlr−/− ± GW (12 weeks) | ↓ aortic root lesion area with GW | ||
[94] | WD-fed Ldlr−/− ± T09 (oral gavage, 6 weeks) | T09: ↓ en face and aortic root lesion area, ↓ MΦ content, ↑ collagen content | ||
[101] | WD-fed Apoe*3Leiden Tg (18 weeks) + cholesterol-depleted diet ± T09 (8 weeks) | T09: ↓ aortic root lesion area, ↓ MΦ content | LXR activation promotes plaque regression | |
[102] | WD-fed Ldlr−/− (6 weeks) + chow ± T09 (3 weeks) | T09: ↓ aortic root lesion area | ||
[90] | WD-fed Apoe−/−, Lxrα−/−Apoe−/− ± GW (11 weeks) | ↑ aortic root lesion area of Lxrα−/−Apoe−/− compared to Apoe−/− | Basal LXRβ does not compensate for loss of LXRα w.r.t. lesion development; however, activation of LXRβ ↓atherosclerotic plaques in the absence of LXRα | |
GW ↓ aortic root lesion area in Apoe−/− and Lxrα−/−Apoe−/− | ||||
[91] | WD-fed Ldlr−/−, Lxrα−/−Ldlr−/−, Lxrβ−/− Ldlr−/− ± T09 (12 weeks) | ↑ aortic root lesion area in Lxrα−/−Ldlr−/− vs. Ldlr−/− | ||
T09: ↓ aortic root lesion area in Ldlr−/−, Lxrα−/−Ldlr−/−, and Lxrβ−/− Ldlr−/− | ||||
[147] | WD-fed Ttc39b−/− vs. WT | Ttc39b−/−: ↓ steatohepatitis, cholesterol absorption, LXRα ubiquitination, ↑ HDL cholesterol | Increasing LXRα stability in the liver promotes its anti-atherogenic effects, while preventing negative effects associated with LXR activation | |
WD-fed Ttc39b−/− Ldlr−/− vs. Ldlr−/− | ↓ en face lesion area in Ttc39b−/−Ldlr−/− vs. Ldlr−/− | |||
[136] | Sprague–Dawley rats + STZ ± T09 | T09: ↓ en face lesion area, aortic intimal senescence | LXR decreases aortic endothelial cell senescence, decreasing atherosclerosis | |
Bone marrow transplant studies 3 | ||||
[92] | 1) Apoe−/− 2) WT 3) Lxrαβ−/− 4) Ldlr−/− 5) WT 6) Lxrαβ−/− | ➔ Apoe−/− ➔ Apoe−/− ➔ Apoe−/− ➔ Ldlr−/− ➔ Ldlr−/− ➔ Ldlr−/− | ↑ en face lesion area in Apoe−/− and Ldlr−/− mice receiving Lxrαβ−/− BM (Apoe−/−: 3 > 1 > 2; Ldlr−/−: 6 > 4,5) | Cholesterol efflux in macrophages is responsible for the LXR-mediated effects on reducing atherosclerotic lesions |
[94] | 1) Ldlr−/− 2) WT 3) Lxrαβ−/− | ➔ Ldlr−/− ± T09 ➔ Ldlr−/− ± T09 ➔ Ldlr−/− ± T09 | T09: ↓ en face lesion area from WT and Ldlr−/− donors | |
[102] | 1) WT ➔ Apoe−/− (3 days WD-early lesion) 2) WT ➔ Apoe−/− (3 weeks WD-advanced lesion) After BMT, recipients switched to chow ± T09 | T09: ↓ early and late aortic root lesion area, ↓ MΦ content | LXR activation promotes plaque regression | |
[103] | WD-fed Apoe−/− ± T09 | T09: ↓ aortic arch MΦ content | ||
Aortic Arch transplants to WT mice after the following BMTs and 16 weeks WD: | ↑ Aortic plaque lesion area and monocyte area of mice from Lxrα−/− Apoe−/− or Lxrβ−/− Apoe−/− donors (2, 3 > 1) | |||
1) Apoe−/− 2) Lxrα−/−Apoe−/− 3) Lxrβ−/−Apoe−/− | ➔ Apoe−/− ➔ Apoe−/− ➔ Apoe−/− | |||
[91] | 1) Ldlr−/− 2) Lxrα−/−Ldlr−/− 3) Ldlr−/− 4) Lxrα−/−Ldlr−/− | ➔ Ldlr−/− ➔ Ldlr−/− ➔ Lxrα−/−Ldlr−/− ➔ Lxrα−/−Ldlr−/− | ↑ en face lesion area in 2 vs. 1 ↑ en face lesion area in 4 vs. 2 ↑ en face lesion area in 4 vs. 3 ↑ en face lesion area in 3 vs. 1 | LXRα also has anti-atherogenic effects in non-hematopoietic cells (3 vs. 1) |
[99] | 1) WT 2) Abca1/g1−/− 3) Abca1/g1−/− 4) Abca1/g1−/−(myeloid) | ➔ Ldlr−/− ± T09 ➔ Ldlr−/− ± T09 ➔ Ldlr−/− ± GW ➔ Ldlr−/− ± GW | T09: ↓ aortic root lesion area in 2 but not 1; ↓ inflammatory cell infiltration in 2 GW: ↓ aortic root lesion area 3 and 4; (greater ↓ in 3 vs. 4) | LXRs can mediate anti-atherogenic effects via BM cells independent of cholesterol efflux from myeloid cells Loss of LXR target genes in BM cells ↑ atherosclerosis Under chow feeding, Abca1/g1−/− from whole BM ↑ lesion area relative to Abca1/g1−/− only in myeloid cells |
[98] | 1) WT and fl/fl 2) Abca1/g1−/− 3) Abca1/g1−/−(myeloid) | ➔ Ldlr−/− (chow) ➔ Ldlr−/− (chow) ➔ Ldlr−/− (chow) | Aortic root lesion area: 2 > 3 > 1 | |
[149] | 1) WT 2) Abca1−/− 3) Apoe−/− 4) Abca1−/−Apoe−/− | ➔ Ldlr−/− ➔ Ldlr−/− ➔ Ldlr−/− ➔ Ldlr−/− | En face and aortic root lesion area: 4 > 3 = 2 > 1 | |
[124] | 1) Ldlr−/− 2) Abca1−/−(myeloid) Ldlr−/− | ➔ Ldlr−/− ➔ Ldlr−/− | Aortic root lesion area: 2 > 1 (chow-fed); 2 = 1 (WD-fed) | |
Tissue-specific gain and loss-of-function studies | ||||
[95] | WD-fed Lxrα-Tg(macrophage) Ldlr−/− vs. Ldlr−/− | Lxrα-Tg(macrophage)Ldlr−/−: ↓ BCA lesion area, ↑ BMDM cholesterol efflux, ↓ BMDM nitric oxide production | Macrophage OE of LXRs ↓ lesion area | |
[96] | Lxrα−/−(liver) vs. WT ± T09 | Lxrα−/−(liver): ↓ T09-induced increases in circulating triglycerides & cholesterol excretion Lxrα−/−(liver): ↓ T09-induced decrease in intestinal cholesterol absorption | Hepatic LXRα is required for agonist-mediated RCT but not ↓ atherosclerosis, whereas intestinal LXRα OE does facilitate RCT and ↓ atherosclerosis | |
[96] | WD-fed Lxrα−/−(liver) Ldlr−/− vs. Ldlr−/− ± T09 | T09: ↓ en face lesion area in both genotypes | ||
[97] | WD-fed Lxrα-Tg(intestine) vs. WT | Lxrα-Tg(intestine): ↓ hepatic cholesterol & triglycerides, ↑ circulating VLDL triglycerides, ↑ HDL cholesterol | ||
[97] | WD-fed Lxrα-Tg(intestine) Ldlr−/− vs. Ldlr−/− | Lxrα-Tg (intestine)Ldlr−/−: ↓ en face & aortic sinus lesion area | ||
[143] | Carotid artery injury in Sprague–Dawley rats ± T09 | T09: ↓ neointimal formation | LXR target genes can also affect non-hematopoietic cells (i.e., endothelial, smooth muscle) to ↓ atherogenesis | |
[140] | 1) WD-fed WT 2) WD-fed Abca1−/− 3) WD-fed Abcg1−/− 4) WD-fed Abca1−/−Abcg1−/− | Aortic eNOS-caveolin interaction: 4 > 3 > 2 > 1 | ||
[138] | Abcg1−/− vs. WT | Abcg1−/−: ↑ monocyte adherence to aortic endothelium | ||
[141] | Abca1/g1−/−(endothelial)Ldlr−/− vs. Ldlr−/− | Abca1/g1−/−(endothelial): ↑ en face and aortic root lesion area, ↑ MΦ content, ↑ monocyte recruitment, ↑ LPS-induced endothelial expression of pro-inflammatory and adhesion molecules | ||
LncRNAs | ||||
[145] | Chow-fed Ad-LeXis vs. Ad-GFP | Ad-LeXis: ↓ plasma cholesterol, hepatic cholesterol biosynthetic gene expression | LncRNA targets of LXRs work to enhance cholesterol efflux and repress cholesterol synthesis, together enhancing the anti-atherogenic effects of LXRs | |
WD-fed LeXis−/− vs. WT | LeXis−/−: ↑ hepatic cholesterol | |||
[146] | BMT3: 1) WT ➔ Ldlr−/− 2) MeXis−/− ➔ Ldlr−/− | MeXis−/−: ↑ en face lesion area, ↓ aortic MΦ Abca1 |
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Rasheed, A.; Cummins, C.L. Beyond the Foam Cell: The Role of LXRs in Preventing Atherogenesis. Int. J. Mol. Sci. 2018, 19, 2307. https://doi.org/10.3390/ijms19082307
Rasheed A, Cummins CL. Beyond the Foam Cell: The Role of LXRs in Preventing Atherogenesis. International Journal of Molecular Sciences. 2018; 19(8):2307. https://doi.org/10.3390/ijms19082307
Chicago/Turabian StyleRasheed, Adil, and Carolyn L. Cummins. 2018. "Beyond the Foam Cell: The Role of LXRs in Preventing Atherogenesis" International Journal of Molecular Sciences 19, no. 8: 2307. https://doi.org/10.3390/ijms19082307