Table 1.
Genes that participate in the intracellular cholesterol traffic and cholesterol homeostasis and affect the efflux of cholesterol to extracellular acceptors. Stimulation of cholesterol efflux: observed as inhibition for knockdown/knockout or stimulation for overexpression; inhibition of cholesterol efflux: observed as stimulation for knockdown/knockout or inhibition for overexpression.
| Gene | Description | Cell(a) | Acceptor | Reference |
|---|---|---|---|---|
| Stimulation of cholesterol efflux | ||||
|
| ||||
| ABCA1 (ATP-binding cassette transporter A1) | Mediates cholesterol efflux | MPM, THP-1, Huh7.5 (hepatoma cells), human foreskin fibroblasts | apoA-I | [29–31] |
| BHK expressing ABCA1 | Mβ-CD | [32] | ||
| ABCG1 (ATP-binding cassette transporter G1) | Mediates cholesterol efflux | J774, THP-1 | HDL | [33] |
| (b) ARF6 (ADP-ribosylation factor 6) | A GTP-binding protein of the Ras family; regulates endocytosis and endocytic recycling of plasma membrane proteins | Cholesterol-depleted RAW 264.7 | apoA-I | [15] |
| BIG1 (Brefeldin A-inhibited guanine nucleotide-exchange protein 1) | Mediates intracellular vesicular trafficking | HepG2 | apoA-I | [34] |
| CANX (Calnexin) | An integral ER membrane calcium-binding lectin-like chaperone | HeLa expressing ABCA1, THP-1 | apoA-I | [35] |
| CAV1 (Caveolin-1) | A scaffolding protein; binds cholesterol; required to formation of caveolae | RAW 264.7 | HDL | [17, 36] |
| HepG2, THP-1 | apoA-I | [36, 37] | ||
| HepG2, fibroblasts | plasma | [36, 38] | ||
| (b) CDC42 (Cell Division Cycle 42) | A GTPase of the Rho family; regulates endocytosis and endocytic recycling of plasma membrane proteins | Cholesterol-depleted RAW 264.7 | apoA-I | [15] |
| CTH (Cystathionine γ-lyase) | Produces endogenous H2S, induces ABCA1 expression by activation of PI3K/AKT pathway | THP-1 | apoA-I, HDL | [39] |
| CTSD (Cathepsin D) | A lysosomal proteinase, activated by ceramide | J774, CHO | apoA-I | [40] |
| (b) DNM2 (Dynamin-2) | A GTPase; regulates endocytosis and endocytic recycling of plasma membrane proteins | Cholesterol-depleted RAW 264.7 | apoA-I | [15] |
| HNF4A (Hepatocyte nuclear factor 4α) | A nuclear transcription factor; required for early liver development and expression of many liver-specific genes; induces expression of ABCA1 | JHH-5 cells (human hepatoma) | apoA-I | [41] |
| ELAVL1 (ELAV-like protein 1 aka Human antigen R aka HuR) |
RNA binding protein; modulates the stability and translational efficiency of mRNAs; promote ABCA1 translation | THP-1 | apoA-I | [42] |
| NPC1 (Niemann-Pick disease, type C1) | Mediates cholesterol trafficking from late endosomes and lysosomes | MPM | HDL2 | [16] |
| OSBPL6 (Oxysterol-binding protein-like 6; aka ORP6) | Participates in cholesterol trafficking between endosomes and endoplasmic reticulum; a target for miR-33 and miR-27b | THP-1, HepG2 | apoA-I, HDL (THP-1, n.d. for HepG2) | [1] |
| PIM1 (Proto-Oncogene, Serine/Threonine Kinase) | Serine/threonine-protein kinase, phosphorylates ABCA1 that retards its degradation | HepG2 | apoA-I | [43] |
| PIP5K1A (Phosphatidylinositiol-5-phosphate 4-kinase α) | Synthesizes phosphatidylinositol 4,5-bisphosphate (PI[4,5]P2) from phosphatidylinositol 4-phosphate (PI4P) | RAW264.7, HEK293 expressing ABCA1 | apoA-I | [44] |
| PPARG (Peroxisome proliferator-activated receptor γ) | A nuclear receptor that regulates lipid and glucose metabolism; induces ABCG1 expression | mBMDM | apoA-I | [45] |
| RAB8A (Rab8) | A small GTPase of the Ras family; participate in cytoskeletal organization and membrane trafficking; induces ABCA1 | hPBMC | apoA-I | [46] |
| (b) SCD (Stearoyl-coenzyme A desaturase 1) | Converts saturated stearic acid (18:0) to monounsaturated oleic acid (18:1) | RAW 264.7 | HDL, HDL2, HDL3, mouse plasma | [47] |
| SNTB1 (β1-syntrophin) | A structural protein containing PDZ domain that anchors membrane proteins to cytoskeleton; interacts with ABCA1 and promotes its expression | mBMDM, primary human fibroblasts | apoA-I | [48] |
| STAR (Steroidogenic acute regulatory protein, StAR) | Transports cholesterol to the inner mitochondrial membrane to sterol 27-hydroxylase. Activates LXRs and promotes expression of ABCA1. | RAW 264.7 | apoA-I | [49, 50] |
| STARD3 (StAR related lipid transfer domain containing 3) | Endosomal cholesterol transporter; promotes expression of ABCA1 | THP-1 | apoA-I | [51] |
| TSPO (Translocator protein) | A small (18 kDa) integral membrane mitochondrial trafficking protein; participates in cholesterol transport, interacts with StAR; promotes expression of ABCA1 | THP-1 | apoA-I, HDL, serum | [52] |
| US28 | A cytomegalovirus (HCMV) protein; activates CDC42; responsible for restructuring of lipid rafts in the host cells | human foreskin fibroblasts | apoA-I | [31] |
| UTRN (Utrophin) | A scaffold protein that interacts with syntrophins and actin cytoskeleton; promotes ABCA1 expression | primary human fibroblasts | apoA-I | [48] |
|
| ||||
| Inhibition of cholesterol efflux | ||||
|
| ||||
| ACSL1 (Acyl-CoA synthetase 1) | A key enzyme mediating synthesis of fatty acyl-CoA esters in macrophages | J774 | apoA-I | [53] |
| ADIPOR2 (Adiponectin receptor 2) | Adiponectin regulates fatty acid oxidation and other metabolic processes. The receptor suppresses expression of ABCA1, ABCG1 | THP-1 | apoA-I, HDL | [54] |
| (b) ARF6 (ADP-ribosylation factor 6) | A GTP-binding protein of the Ras family; regulates endocytosis and endocytic recycling of plasma membrane proteins | RAW 264.7 | apoA-I, mBMDM | [15] |
| (b) CDC42 (Cell Division Cycle 42) | A GTPase of the Rho family; regulates endocytosis and endocytic recycling of plasma membrane proteins | RAW 264.7 | apoA-I | [15] |
| (b) DNM2 (Dynamin-2) | A GTPase; regulates endocytosis and endocytic recycling of plasma membrane proteins | RAW 264.7 | apoA-I | [15] |
| ENTPD1 (Ectonucleoside triphosphate diphosphohydrolase-1 aka CD39) | Anchored to plasma membrane and hydrolysis extracellular ATP, which is increased when ABCA1 is highly expressed | RAW 264.7, BHK expressing ABCA1 | apoA-I | [55] |
| IRAK1 (Interleukin-1 receptor-associated kinase-1) | Participates in signaling via TLR (Toll-like receptors)/IL-1R (interleukin 1 receptor) | THP-1 | apoA-I, HDL | [56] |
| LCK (Lymphocyte-specific protein tyrosine kinase) | A tyrosine kinase of Src family; participates in T-cell receptor signaling | Jurkat cells | apoA-I | [57] |
| LPL (Lipoprotein lipase) | A secreted enzyme facilitating the hydrolysis of triglycerides in chylomicrons | THP-1 | apoA-I | [58] |
| OSBPL8 (OSBP-related protein 8 ala ORP8) | An endoplasmic reticulum protein that binds 25-hydroxycholesterol and other lipid molecules and transfer them between ER and PM; inhibits ABCA1 expression | THP-1 | apoA-I | [59] |
| PLIN2 (Perilipin 2 aka Adipophilin) | Protein, associated with intracellular lipid droplets; a marker of lipid accumulation | THP-1 | apoA-I | [60] |
| PTX3 (Pentraxin 3) | A member of the pentraxin family together with short pentraxins, such as C-reactive protein and serum amyloid P component; releases in response to inflammation; inhibits ABCA1 expression | THP-1 | apoA-I | [61] |
| ROCK2 (Rho Associated Coiled-Coil Containing Protein Kinase 2) | Serine-threonine protein kinase; involved in the regulation of the actin cytoskeleton | mBMDM | apoA-I | [45] |
| (b) SCD1 (Stearoyl-coenzyme A desaturase 1) | converts saturated stearic acid (18:0) to monounsaturated oleic acid (18:1) | THP-1 | no acceptor | [62] |
| SCP2 (Sterol carrier protein-2) | Mediates cholesterol and phospholipid intracellular trafficking | L-cell fibroblasts | HDL | [63] |
| SPTLC1 (Serine palmitoyltransferase long chain base subunit 1) | The key enzyme in sphingolipid biosynthesis; blocks the exit of ABCA1 from the endoplasmic reticulum | primary human fibroblasts, HEK 293-EBNA-T cells expressing ABCA1 | apoA-I | [64] |
| SREBP2 (Sterol-responsive element-binding protein 2) | A transcription factor regulating cholesterol synthesis and uptake; N-terminus is an active form of SREBP2; inhibits ABCA1 expression | HUVEC | apoA-I | [65] |
| TMEM55B (Transmembrane Protein 55B) | A specific PIP2 phosphatase that converts PIP2 (phosphatidylinositol (4,5) bis-phosphate) to PI5P phosphatidylinositol 5-phosphate) | RAW264.7 | apoA-I | [44] |
| TNFRSF25 (TNF receptor superfamily member 25 aka Death receptor 3) | A cell surface receptor of TNF-like protein 1A (TL1A); highly expressed in foam cells in atherosclerotic plaques; TL1A inhibits expression of ABCA1 and ABCG1 | THP-1, hPBMC | apoA-I | [66] |
| ZNF202 (Zinc finger protein 202) | a transcriptional repressor of ABCA1 and ABCG1 | RAW 264.7 | HDL3 | [67] |
(a)In some cases, cells were treated to differentiate to macrophages (e.g., by PMA (phorbol 12-myristate 13-acetate) or colony-stimulating factor GM-CSF), to induce expression of ABCA1 (e.g., by cpt-cAMP, TO-901317, or 22-OH+9cRA), and transformed to foam cells (e.g., by acLDL).
(b)denotes that the gene has both stimulating and inhibiting effect depending on the type of cells and/or cholesterol acceptor.
hPBMC: human peripheral blood mononuclear cells; HUVEC: human umbilical vein endothelial cells; mBMDM: mouse bone-marrow-derived macrophage; MPM: mouse peritoneal macrophage; Mβ-CD: methyl β cyclodextrin.