Liver X Receptors Regulate Cholesterol Metabolism and Immunity in Hepatic Nonparenchymal Cells
Abstract
:1. Introduction
2. Hepatic Nonparenchymal Cells
2.1. Two Types of Macrophages: Resident Kupffer Cells and Bone Marrow-Derived Macrophages (BMDMs)
2.2. Hepatic Stellate Cells (HSCs)
2.3. Liver Sinusoidal Endothelial Cells (LSECs)
2.4. Natural Killer (NK) Cells and Natural Killer T (NKT) Cells
3. Cholesterol Metabolism and Function of Hepatic Nonparenchymal Cells in Liver Diseases
3.1. NAFLD and NASH in Hypercholesterolemic Mice
3.2. Acute Hepatic Inflammation
3.3. Hepatic Fibrosis and Hepatocellular Carcinoma (HCC)
3.4. Anti-Tumor Immunity
4. Oxysterol Receptors LXRα and LXRβ
4.1. Regulation of Lipid Metabolism
4.2. Anti-Inflammatory Function in Immune Cells
5. LXR Function in Hepatic Nonparenchymal Cells in Liver Diseases
5.1. Expression of LXRs in Liver Nonparenchymal Cells
5.2. Acute Hepatic Inflammation
5.3. Effects of LXR Activation or Absence in NAFLD and NASH
5.4. Hepatic Fibrosis
5.5. Wilson Disease
6. Concluding Remarks
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
NAFLD | nonalcoholic fatty liver diseases |
NASH | nonalcoholic steatohepatitis |
LXR | liver X receptor |
HSC | hepatic stellate cell |
LSEC | liver sinusoidal endothelial cell |
BMDM | bone marrow-derived macrophage |
NK | natural killer |
NKT | natural killer T |
TLR | Toll-like receptor |
TREM2 | triggered receptor expressed on myeloid cells 2 |
MerTK | Mer receptor tyrosine kinase |
α-SMA | α-smooth muscle actin |
Col1a1 | collagen α1(I) |
HCC | hepatocellular carcinoma |
α-GalCer | α-galactosylceramide |
IL | interleukin |
iNKT | invariant natural killer T |
CXCR6 | C-X-C motif chemokine receptor 6 |
HCD | high-cholesterol diet |
HFCD | high-fat and high-cholesterol diet |
HFD | high-fat diet |
LPS | lipopolysaccharide |
BDL | bile duct ligation |
CCl4 | carbon tetrachloride |
MNC | mononuclear cell |
RXR | retinoid X receptor |
ABC | ATP-binding cassette |
CCL | C-C chemokine ligand |
TNF | tumor necrosis factor |
PNPLA3 | patatin-like phospholipase domain-containing protein 3 |
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Animal | LXR | Acute or Chronic | Treatment | Target Cells | Findings | Ref |
---|---|---|---|---|---|---|
Mouse (WT, LXRα/β-KO) | Absence | No treatment | F4/80loCD11b+ Kupffer cells/macrophages | F4/80loCD11b+ cells↑ Inflammatory gene expression in hepatic MNCs↑ | [80] | |
Rat (WT) | Activation | Acute | GW3965 (0.1 or 0.3 mg/kg) LPS (5 mg/kg)/ Peptidoglycan (1 mg/kg) for 1–6 h | Kupffer cells/macrophages | Plasma TNF-α, PGE2, ALT, bilirubin ↓ Hepatocyte injury ↓ | [79,84] |
Mouse (WT) | Activation | Acute | HFD (8 weeks), T0901317 (30 mg/kg for 7 days) LPS (50 μg/mouse) | Kupffer cells/macrophages | Plasma AST/ALT ↓ Hepatic TNF-α, iNOS expression ↓ Hepatic PI3K, NF-κB, MAPK signaling ↓ | [85] |
Mouse (WT) | Activation | Acute | T0901317 (50 mg/kg for 12 h) LPS (10 mg/kg for 12 h) | Kupffer cells/macrophages | Leukocyte infiltration ↓ Plasma AST/ALT ↓ Plasma, supernatant of Kupffer cells TNF-α, IFN-β, IL-1β ↓, IL-10 ↑ | [86] |
Mouse (WT, LXRα-KO) | Absence | Chronic (NASH) | HFCD (4 weeks) | Kupffer cells/macrophages iNKT cells | F4/80+CD68+CD11b+ cells ↑ iNKT cells ↓ Plasma AST/ALT ↑ | [87] |
Mouse (WT, LXRα-KO) | Absence | Chronic (NASH) | HFCD (4 weeks) LPS (2.5 mg/kg, 1–6 h) | Kupffer cells/macrophages | Leukocyte accumulation ↑ Plasma TNF-α, IFN-γ, IL-12, CCL2, AST/ALT ↑ | [87] |
Mouse (WT, LXRα-KO) | Absence | Chronic (NASH) | HFCD (4 weeks) α-GalCer, 0.1 mg/kg, 1–72 h) | iNKT cells | Plasma IL-4, IFN-γ ↓ | [87] |
Mouse (WT, LXRα-KO) | Absence | Chronic (NASH) | HFCD (4 weeks) Con-A, 12.5 mg/kg, 1–72 h) | iNKT cells | Plasma AST/ALT, bilirubin ↓ Hepatocyte necrosis ↓ | [87] |
Mouse (WT, LXRα/β-KO) | Absence | Chronic (Fibrosis) | CCl4 (10%, v/v, twice per week for 4 weeks) | HSCs | Plasma ALT ↑ Col1a1 expression ↑ Fibrosis ↑ | [88] |
Mouse (WT, LXRα/β-KO) | Absence | Chronic (Fibrosis) | Methionine/choline-deficient diet (1 month) | HSCs | Col1a1 expression ↑ Fibrosis ↑ | [88] |
Mouse (WT) | Activation | Chronic (Fibrosis) | T0901317 (50 mg/kg, daily for 1 week) CCl4 (10 %, v/v, twice per week for 1 month) | LSECs | CD31+ LSEC capillarization ↓ Hepatic F4/80+ cells ↓ Fibrotic score ↓ | [89] |
Mouse (WT, LXRα-KO) | Absence | Chronic (Fibrosis) | CCl4 (10%, v/v, twice per week for 1 month) | LSECs | CD31+ LSEC capillarization ↑ Hepatic F4/80+ cells ↑ Fibrotic score ↑ | [89] |
Mouse (Atp7b-KO) | Activation | Chronic (Wilson disease) | T0901317 (50 mg/kg, thrice per week for 8 weeks) | Kupffer cells/macrophages HSCs | Hepatic inflammatory or fibrotic genes ↓ Plasma AST/ALT ↓ | [90] |
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Endo-Umeda, K.; Makishima, M. Liver X Receptors Regulate Cholesterol Metabolism and Immunity in Hepatic Nonparenchymal Cells. Int. J. Mol. Sci. 2019, 20, 5045. https://doi.org/10.3390/ijms20205045
Endo-Umeda K, Makishima M. Liver X Receptors Regulate Cholesterol Metabolism and Immunity in Hepatic Nonparenchymal Cells. International Journal of Molecular Sciences. 2019; 20(20):5045. https://doi.org/10.3390/ijms20205045
Chicago/Turabian StyleEndo-Umeda, Kaori, and Makoto Makishima. 2019. "Liver X Receptors Regulate Cholesterol Metabolism and Immunity in Hepatic Nonparenchymal Cells" International Journal of Molecular Sciences 20, no. 20: 5045. https://doi.org/10.3390/ijms20205045