The ABCA2 Transporter: Intracellular Roles in Trafficking and Metabolism of LDL-Derived Cholesterol and Sterol-Related Compounds

Mack, Jody T.; Townsend, Danyelle M.; Beljanski, Vladimir; Tew, Kenneth D.

doi:10.2174/138920007779315044

Cited by 44 publications

(25 citation statements)

References 121 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Even though the role of NPC1L1 is still debatable, one can theorize that an increase in NPC1L1 could aide in enhanced sterol movement (from LDL or HDL) across trophoblasts (71). SCP-2/x and ABCA2 (14,15) were also expressed by the placenta, and as in other tissues, expres-sion appeared unaffected by placental cholesterol concentrations (72,73).…”

Section: Placentamentioning

confidence: 99%

“…The ester bonds are hydrolyzed, possibly through one of the cytosolic esterases. Once internalized, sterols from either source are transported by way of a number of putative transport proteins, including NPC1 Like 1 (NPC1L1), sterol carrier protein (SCP)-x/2, and ABCA2 (14,15) [reviewed in (16,17)]. The sterol is secreted from cells as lipoprotein particles or apoE:lipid complexes or effluxed by way of ABCA1, ABCG1, or ABCG5/8 [reviewed in (18)].…”

mentioning

confidence: 99%

See 1 more Smart Citation

Transport of maternal cholesterol to the fetus is affected by maternal plasma cholesterol concentrations in the Golden Syrian hamster

Burke

Colvin

Myatt

et al. 2009

Journal of Lipid Research

View full text Add to dashboard Cite

The fetus has a high requirement for cholesterol and synthesizes cholesterol at elevated rates. Recent studies suggest that fetal cholesterol also can be obtained from exogenous sources. The purpose of the current study was to examine the transport of maternal cholesterol to the fetus and determine the mechanism responsible for any cholesterol-driven changes in transport. Studies were completed in pregnant hamsters with normal and elevated plasma cholesterol concentrations. Cholesterol feeding resulted in a 3.1-fold increase in the amount of LDL-cholesterol taken up by the fetus and a 2.4-fold increase in the amount of HDL-cholesterol taken up. LDL-cholesterol was transported to the fetus primarily by the placenta, and HDL-cholesterol was transported by the yolk sac and placenta. Several proteins associated with sterol transport and efflux, including those induced by activated liver X receptor, were expressed in hamster and human placentas: NPC1, NPC1L1, ABCA2, SCP-x, and ABCG1, but not ABCG8. NPC1L1 was the only protein increased in hypercholesterolemic placentas. Thus, increasing maternal lipoprotein-cholesterol concentrations can enhance transport of maternal cholesterol to the fetus, leading to 1) increased movement of cholesterol down a concentration gradient in the placenta, 2) increased lipoprotein secretion from the yolk sac (shown previously), and possi- Cholesterol is essential for normal fetal development. Possibly the most noted role of cholesterol is as a structural component of membranes. Sterols are also the precursor for bile acids, steroid hormones, and oxysterols, which are all synthesized by the fetus and regulate various cellular processes. Cholesterol is also required for activation of sonic hedgehog (Shh), a protein involved in brain development, and for propagation of the Shh signal (1, 2). Cholesterol is obtained endogenously by de novo synthesis and exogenously by transfer of maternal cholesterol to the fetus. Interestingly, maternal plasma triglyceride and cholesterol concentrations increase during pregnancy in humans (3, 4), possibly an adaptation to maternal and fetal needs. However, whether these changes in maternal lipoprotein concentrations result in increased transport of maternal cholesterol to the fetus is unclear.Since the fetus does not come in direct contact with the maternal circulation, maternal cholesterol destined for the fetus must initially be taken up by the placenta and yolk sac prior to transport and delivery to the fetus. Indeed, the placenta and yolk sac take up maternal LDL-and HDLcholesterol at relatively elevated rates compared with other peripheral tissues (5). LDL is taken up by the LDL receptor (LDLR), which is expressed abundantly in the placenta but expressed at low levels, if at all, in the yolk sac (5, 6). LDL-derived sterol is transported to the lysosome/endosome pathway where the ester bond is hydrolyzed (7). The unesterified cholesterol is then transported by NiemannThese studies were supported by grants HD34089 (LAW) and GM31651 (FS) from the...

show abstract

Section: Placentamentioning

confidence: 99%

mentioning

confidence: 99%

Transport of maternal cholesterol to the fetus is affected by maternal plasma cholesterol concentrations in the Golden Syrian hamster

Burke

Colvin

Myatt

et al. 2009

Journal of Lipid Research

View full text Add to dashboard Cite

show abstract

“…3). Besides ACAT-1, macrophage NCEH, ABCA1, [134][135][136][137] ABCG1, 135,138,139 Apo A-1 140,141 also play an important role in macrophage cholesterol transport and foam cell formation (Fig. 3).…”

Section: S C a V E N G E R R E C E P T O R U P R E G U L A T I O N mentioning

confidence: 99%

Macrophages: An elusive yet emerging therapeutic target of atherosclerosis

Tiwari

Singh

Barthwal

2007

Medicinal Research Reviews

139

120

View full text Add to dashboard Cite

Macrophages are central to the initiation and progression of atherosclerosis and thus can be very appropriate targets for therapy. Cell adhesion molecules mediating monocytes recruitment to the endothelium are attractive therapy targets and their inhibitors are in clinical trials. Macrophage scavenger receptors like SR-A and CD-36 mediate foam cell formation by facilitating the uptake of modified lipids. Peroxisome proliferator-activated receptors (PPAR), liver X receptor (LXR)-mediated signaling, mitogen-activated protein kinase (MAPK) induced phosphorylation events seem to play an important role in this phenomenon. Proteins affecting macrophage cholesterol metabolism and transport, including ATP-binding cassette (ABC) A1, ABCG1, acylCoA:cholesterol acyltransferase (ACAT), apolipoprotein A-1 (ApoA-1), neutral cholesteryl ester hydrolase (NCEH) also regulate foam cell formation and are being developed as therapeutic targets by many pharmaceutical companies. Macrophage proliferation and apoptosis are important events controlling inflammatory response, plaque vulnerability, and destabilization. Free cholesterol (FC) activates the macrophage endoplasmic reticulum (ER) stress pathway and apoptosis. Free radicals and nitric oxide also modulate macrophage foam cell formation and apoptosis. Various antioxidants like AGI-1067 and BO-653 are in clinical trials for atherosclerosis treatment. Macrophage matrix metalloproteinase's (MMP's) play a significant role in weakening and rupture of plaques. Efforts are on to develop isoform specific MMP inhibitor. CD-14, MMP-3, ABCA1, Toll-like receptor-4 (TLR-4), lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), arachidonate lipoxygenase-15 (ALOX-15), and Connexin37 polymorphisms and macrophage dysfunction signify their importance in atherosclerosis. Deciphering the role of macrophages in regulating dyslipidemia and inflammation during atherosclerosis is important for developing them as therapeutic targets. ß 2007 Wiley Periodicals, Inc. Med Res Rev, 28, No. 4, 483-544, 2008

show abstract

“…As shown in Table 1, a number of genes involved in apoptosis was down-regulated in RST2 cells as compared with Daudi cells, such as PKR (EIF2AK2), STAT1, PML, MCL1, as well as genes that play a role in sterol/steroid metabolism (p Ͻ 0.004) and fatty acid ␤-oxidation (p Ͻ 0.01). Steroid metabolism is implicated in multidrug resistance especially against various chemotherapeutic agents (19,20).…”

Section: Characterization Of Ifn-resistant Rst2mentioning

confidence: 99%

Interferon-resistant Daudi Cell Line with a Stat2 Defect Is Resistant to Apoptosis Induced by Chemotherapeutic Agents

Fan

Kim

et al. 2009

Journal of Biological Chemistry

View full text Add to dashboard Cite

Interferon-␣ (IFN␣) has shown promise in the treatment of various cancers. However, the development of IFN resistance is a significant drawback. Using conditions that mimic in vivo selection of IFN-resistant cells, the RST2 IFN-resistant cell line was isolated from the highly IFN-sensitive Daudi human Burkitt lymphoma cell line. The RST2 cell line was resistant to the antiviral, antiproliferative, and gene-induction actions of IFN␣. Although STAT2 mRNA was present, STAT2 protein expression was deficient in RST2 cells. A variant STAT2 mRNA, which resulted from alternative splicing within the intron between exon 19 and 20, was expressed in several human cell lines but at relatively high levels in RST2 cells. Most importantly, the RST2 line showed an intrinsic resistance to apoptosis induced by a number of chemotherapeutic agents (camptothecin, staurosporine, and doxorubicin). Expression of STAT2 in RST2 cells not only rescued their sensitivity to the biological activities of IFNs but also restored sensitivity to apoptosis induced by these chemotherapeutic agents. The intrinsic resistance of the RST2 cells to IFN as well as chemotherapeutic agents adds a new dimension to our knowledge of the role of STAT2 as it relates to not only biological actions of IFN but also resistance to chemotherapyinduced apoptosis. IFN2 ␣/␤ regulates a number of cellular responses, such as proliferation, differentiation, and development (1). Although IFN triggers the death of some tumor cells by inducing proapoptotic proteins (tumor necrosis factor-related apoptosis-inducing ligand, PKR, etc.), IFN also promotes cell survival through a nuclear factor B-dependent pathway (2-4). IFN is used to treat various human malignancies (chronic myeloid leukemia, non-Hodgkin lymphomas, Kaposi sarcoma, hairy cell leukemia, multiple myeloma, and malignant melanoma), viral infections, as well as various other diseases (5, 6). However, only a fraction of patients are responsive to IFN therapy, and many patients eventually develop resistance after chronic IFN exposure. The underlying mechanism for IFN resistance is still unclear, but it is reasonable to suggest that genetic variation and selection during prolonged IFN exposure may reflect IFN signaling defects.IFN binds to its cell surface receptor resulting in the activation of JAK1 and TYK2 nonreceptor protein-tyrosine kinases, which phosphorylate STAT proteins (7). Phosphorylated STAT1 and STAT2 in a complex with IRF9 bind to a conserved IFN stimulus-response element (ISRE) present in the promoters of hundreds of IFN-stimulated genes (ISGs) inducing their expression. Mutant cell lines with defined signaling defects have made significant contributions in elucidating the IFN-activated JAK/STAT signal transduction pathway (7,8). Such IFN-resistant mutants were isolated after multiple rounds of chemical mutagenesis and selection of IFN-resistant mutants. However, this procedure does not mimic in vivo what happens to patients who are subjected to long term IFN treatment. Moreover, these IFN-resistant cells ...

show abstract

The ABCA2 Transporter: Intracellular Roles in Trafficking and Metabolism of LDL-Derived Cholesterol and Sterol-Related Compounds

Cited by 44 publications

References 121 publications

Transport of maternal cholesterol to the fetus is affected by maternal plasma cholesterol concentrations in the Golden Syrian hamster

Transport of maternal cholesterol to the fetus is affected by maternal plasma cholesterol concentrations in the Golden Syrian hamster

Macrophages: An elusive yet emerging therapeutic target of atherosclerosis

Interferon-resistant Daudi Cell Line with a Stat2 Defect Is Resistant to Apoptosis Induced by Chemotherapeutic Agents

Contact Info

Product

Resources

About