Intracellular and Plasma Membrane Events in Cholesterol Transport and Homeostasis

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	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]
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]
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]
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 (PIP2) 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]
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]
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]
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]
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]
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]

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).
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.