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Background: ATP‐binding cassette subfamily G member 1 is mostly known as a transporter for intracellular cholesterol efflux, and a number of studies indicate that ABCG1 also functions actively in tumor initiation and progression. This review aimed to provide an overall review of how ABCG1 acts in tumor progression. Method: A comprehensive searching about ABCG1 and tumor was conducted up to November 2023 using proper keywords through databases including PubMed and Web of Science. Result: Overall, ABCG1 plays a crucial role in the development of multiple tumorigenesis. ABCG1 enhances tumor‐promoting ability through conferring stem‐like properties to cancer cells and mediates chemoresistance in multiple cancers. Additionally, ABCG1 may act as a kinase to phosphorylate downstream molecules and induces tumor growth. In tumor microenvironment, ABCG1 plays a substantial role in immunity response through macrophages to create a tumor‐favoring circumstance. Conclusion: High expression of ABCG1 is usually associated with poor prognosis, which means ABCG1 may be a potential biomarker for early diagnosis and prognosis of various cancers. ABCG1‐targeted therapy may provide a novel treatment for cancer patients. [ABSTRACT FROM AUTHOR]

Background: Abnormal lipid metabolism is involved in the development of osteoarthritis (OA). ATP‐binding cassette protein G1 (ABCG1) is crucial in mediating the outflow of cholesterol, phosphatidylcholine and sphingomyelin and reducing intracellular lipid accumulation. Objective: This study aimed to evaluate whether ABCG1 participates in the abnormal adipogenesis of chondrocytes in osteoarthritic cartilage of temporomandibular joint. Methods: Eight‐week‐old female rats were subjected to unilateral anterior crossbite (UAC) to induce OA in the temporomandibular joint (TMJ). Histochemical staining, immunohistochemical (IHC) staining, and qRT–PCR were performed. Primary condylar chondrocytes of rats were transfected with ABCG1 shRNA or overexpression lentivirus and then stimulated with fluid flow shear stress (FFSS). Cells were collected for oil red O staining, immunofluorescence staining, and qRT–PCR analysis. Results: Abnormal adipogenesis, characterized by increased expression of Adiponectin, CCAAT/enhancer‐binding protein α (Cebpα), fatty acid binding protein 4 (Fabp4) and Perilipin1, was enhanced in the degenerative cartilage of TMJ OA in rats with UAC, accompanied by decreased expression of ABCG1. After FFSS stimulation, we observed lipid droplets in the cytoplasm of cultured cells with increased expression of Adiponectin, Cebpα, Fabp4 and Perilipin1 and decreased expression of ABCG1. Knockdown of Abcg1 induced abnormal adipogenesis and differentiation of condylar chondrocytes. Overexpression of ABCG1 alleviated the abnormal adipogenesis and differentiation of condylar chondrocytes induced by FFSS. Conclusions: Abnormal adipogenesis of chondrocytes and decreased ABCG1 expression were observed in degenerative cartilage of TMJ OA. ABCG1 overexpression effectively inhibits the adipogenesis of chondrocytes and thus alleviates TMJ condylar cartilage degeneration. [ABSTRACT FROM AUTHOR]

The maintenance of cholesterol homeostasis is essential for central nervous system function. Consequently, factors that affect cholesterol homeostasis are linked to neurological disorders and pathologies. Among them, ATP‐binding cassette transporter G1 (ABCG1) plays a significant role in atherosclerosis. However, its role in Alzheimer's disease (AD) is unclear. There is inconsistent information regarding ABCG1's role in AD. It can increase or decrease amyloid β (Aβ) levels in animals' brains. Clinical studies show that ABCG1 is involved in AD patients' impairment of cholesterol efflux capacity (CEC) in the cerebrospinal fluid (CSF). Lower Aβ levels in the CSF are correlated with ABCG1‐mediated CEC dysfunction. ABCG1 modulates α‐, β‐, and γ‐secretase activities in the plasma membrane and may affect Aβ production in the mitochondria‐associated endoplasmic reticulum (ER) membrane (MAM) cell compartment. Despite contradictory findings regarding ABCG1's role in AD, this review shows that ABCG1 has a role in Aβ generation via modulation of membrane secretases. It is, however, necessary to investigate the underlying mechanism(s). ABCG1 may also contribute to AD pathology through its role in apoptosis and oxidative stress. As a result, ABCG1 plays a role in AD and is a candidate for drug development. [ABSTRACT FROM AUTHOR]

Macrophage‐derived foam cell formation is critical for the initiation and development of atherosclerosis, which contributes to atherosclerotic cardiovascular disease (ASCVD). Glutathione peroxidase 4 (GPX4), a crucial ferroptosis regulator, protects cells from excessive oxidative stress by neutralizing lipid peroxidation. However, the role of macrophage GPX4 in foam cell formation remains unknown. We reported that oxidized low‐density lipoprotein (oxLDL) upregulated GPX4 expression in macrophages. Using the Cre‐loxP system, we generated myeloid cell‐specific Gpx4 knockout (Gpx4myel‐KO) mice. Bone marrow‐derived macrophages (BMDMs) were isolated from WT and Gpx4myel‐KO mice and incubated with modified low‐density lipoprotein (LDL). We found that Gpx4 deficiency promoted foam cell formation and increased the internalization of modified LDL. Mechanistic studies unveiled that Gpx4 knockout upregulated scavenger receptor type A and LOX‐1 expression and downregulated ABCA1 and ABCG1 expression. Collectively, our study lends a novel insight into the role of GPX4 in suppressing macrophage‐derived foam cell formation and suggests GPX4 as a promising therapeutic target to interfere with atherosclerosis‐related diseases. [ABSTRACT FROM AUTHOR]

The effects of interferon‐γ (IFN‐γ) on cholesterol accumulation and the development of foam cells are still unclear. In the present study, we found that IFN‐γ promoted liver X receptor (LXR)‐α degradation through the ubiquitin–proteasome system in macrophages. The process was dependent on its interactions with phosphorylated signal transducer and activator of transcription 1 (p‐STAT1) and protein inhibitor of activated STAT 1 (PIAS1) because both fludarabine and PIAS1 shRNA reversed the decrease in LXR‐α protein expression induced by IFN‐γ. Additionally, IFN‐γ enhanced the interactions of ubiquitin‐conjugating enzyme 9 (UBC9), small ubiquitin‐like modifier (SUMO)‐1 and SUMO‐2/3 with LXR‐α. Moreover, treatment with shRNA specific for them not only reduced LXR‐α polyubiquitination but also reversed the IFN‐γ‐induced decrease in its expression. Two specific sumoylation sites in LXR‐α, K22 and K326, were indispensable for its IFN‐γ‐induced polyubiquitination because the K22R and K326R mutations inhibited the polyubiquitination and degradation of LXR‐α in IFN‐γ‐treated macrophages. In addition, K22R or K326R mutation almost completely restored ATP‐binding cassette subfamily G member 1 (ABCG1)‐mediated cholesterol efflux in IFN‐γ‐treated macrophages. Taken together, these findings indicate that IFN‐γ promotes LXR‐α degradation through a SUMO–ubiquitin‐dependent pathway, which may inhibit cholesterol efflux mediated by ABCG1 from macrophages and promote the development of atherosclerosis. [ABSTRACT FROM AUTHOR]

Atherosclerosis is a chronic inflammatory disease with high mortality worldwide. The reverse cholesterol transport pathway in macrophage plays an important role in the pathogenesis of coronary artery disease (CAD) and is strongly controlled by regulatory factors. The microRNAs can promote or prevent the formation of atherosclerotic lesions by post‐transcriptional regulation of vital genes in this pathway. Therefore, this study was conducted to investigate the relationship between the expression levels of miR‐27a, miR‐329, ABCA1, and ABCG1 genes and serum levels of hs‐CRP, ox‐LDL, and indices of oxidative stress in the patients with established CAD and controls. A total of 84 subjects (42 patients with CAD and 42 controls) were included in this study. Expression levels of miR‐27a‐3p, miR‐329‐3p, ABCA1, and ABCG1 genes in the peripheral blood mononuclear cells (PBMCs) and serum concentration of hs‐CRP and ox‐LDL were measured by real time‐PCR and ELISA, respectively. Also, oxidative stress parameters in the serum were evaluated by ferric‐reducing antioxidant power (FRAP) and malondialdehyde (MDA) assays. ABCA1 and ABCG1 gene expression in PBMC and serum concentration of FRAP were significantly lower in the CAD group compared to the control group. Expression levels of miR‐27a and miR‐329 and serum levels of hs‐CRP, ox‐LDL, and MDA were significantly higher in the CAD group compared to the control group. Serum levels of hs‐CRP, ox‐LDL, and expression level of miR‐27a have inversely related to ABCA1 and ABCG1 gene expression in all the subjects. An increase in the expression levels of miR‐27a and miR‐329 may lead to the progression of atherosclerosis plaque by downregulating the expression of ABCA1 and ABCG1 genes. [ABSTRACT FROM AUTHOR]

Malaria in pregnancy (MiP) induces intrauterine growth restriction (IUGR) and preterm labour (PTL). However, its effects on yolk sac morphology and function are largely unexplored. We hypothesized that MiP modifies yolk sac morphology and efflux transport potential by modulating ABC efflux transporters. C57BL/6 mice injected with Plasmodium berghei ANKA (5 × 105 infected erythrocytes) at gestational day (GD) 13.5 were subjected to yolk sac membrane harvesting at GD 18.5 for histology, qPCR and immunohistochemistry. MiP did not alter the volumetric proportion of the yolk sac's histological components. However, it increased levels of Abcb1a mRNA (encoding P‐glycoprotein) and macrophage migration inhibitory factor (Mif chemokine), while decreasing Abcg1 (P < 0.05); without altering Abca1, Abcb1b, Abcg2, Snat1, Snat2, interleukin (Il)‐1β and C‐C Motif chemokine ligand 2 (Ccl2). Transcripts of Il‐6, chemokine (C‐X‐C motif) ligand 1 (Cxcl1), Glut1 and Snat4 were not detectible. ABCA1, ABCG1, breast cancer resistance protein (BCRP) and P‐gp were primarily immunolocalized to the cell membranes and cytoplasm of endodermic epithelium but also in the mesothelium and in the endothelium of mesodermic blood vessels. Intensity of P‐gp labelling was stronger in both endodermic epithelium and mesothelium, whereas ABCA1 labelling increased in the endothelium of the mesodermic blood vessels. The presence of ABC transporters in the yolk sac wall suggests that this fetal membrane acts as an important protective gestational barrier. Changes in ABCA1 and P‐gp in MiP may alter the biodistribution of toxic substances, xenobiotics, nutrients and immunological factors within the fetal compartment and participate in the pathogenesis of malaria‐induced IUGR and PTL. [ABSTRACT FROM AUTHOR]

Summary: Angiosperm reproductive development is a complex event that includes floral organ development, male and female gametophyte formation and interaction between the male and female reproductive organs for successful fertilization. Previous studies have revealed the redundant function of ATP binding cassette subfamily G (ABCG) transporters ABCG1 and ABCG16 in pollen development, but whether they are involved in other reproductive processes is unknown. Here we show that ABCG1 and ABCG16 were not only expressed in anthers and stamen filaments but also enriched in pistil tissues, including the stigma, style, transmitting tract and ovule. We further demonstrated that pistil‐expressed ABCG1 and ABCG16 promoted rapid pollen tube growth through their effects on auxin distribution and auxin flow in the pistil. Moreover, disrupted auxin homeostasis in stamen filaments was associated with defective filament elongation. Our work reveals the key functions of ABCG1 and ABCG16 in reproductive development and provides clues for identifying ABCG1 and ABCG16 substrates in Arabidopsis. Significance Statement: Our analyses indicate that pistil‐expressed ABCG1 and ABCG16 promote pollen tube growth, and we demonstrate that the retarded pollen tube growth in abcg1 abcg16 double mutant pistils was associated with reduced auxin distribution and auxin flow. Critically, the pollen tube growth defect observed in abcg1 abcg16 pistils was partially rescued by application of exogenous auxin. These findings also provide clues that may help identify ABCG1 and ABCG16 substrates in Arabidopsis. [ABSTRACT FROM AUTHOR]

Background and Aim Abnormal cholesterol metabolism may contribute to the pathogenesis of non-alcoholic steatohepatitis (NASH) and fibrosis. miR-33 and miR-144 regulate adenosine triphosphate binding cassette transporter ( ABCA1) and other target genes involved in cholesterol efflux, fatty acid oxidation and inflammation. We explored relationships between non-alcoholic fatty liver disease (NAFLD) and the hepatic expression of ABCA1/ABCG1, as well as other target genes regulated by miR-33 (carnitine O-octanoyltransferase, CROT and hydroxyacyl-CoA-dehydrogenase β-subunit, HADHB) and miR-144 (toll-like receptor-2, TLR2). Moreover, we evaluated whether the expression of these genes is correlated with miR-33a/b and miR-144 expression in Mexican individuals with morbid obesity. Methods Eighty-four morbidly obese subjects undergoing bariatric surgery were included in this study. Liver biopsies were obtained to measure hepatic triglyceride and free cholesterol contents, as well as ABCA1, ABCG1, CROT, HADHB, TLR2, miR-33a/b and miR-144 expression. Results Hepatic free cholesterol content was significantly increased in NASH as compared to non-NASH subjects, while ABCA1 and ABCG1 protein levels significantly decreased with NASH and fibrosis progression. The relative expression of miR-33a and miR-144 correlated inversely with ABCA1 but not with ABCG1 protein levels. Moreover, both miRNAs increased significantly in NASH individuals. miR-33 target genes CROT and HADHB correlated inversely with miR-33a. However, the expression of these genes was not associated with NASH. Conclusions miR-33a/144 and their target gene ABCA1 may contribute to the pathogenesis of NASH in morbidly obese subjects. [ABSTRACT FROM AUTHOR]

Cell membrane transporters and metabolic enzymes play a crucial role in the transportation of a wide variety of substrates that maintain homeostasis in biological processes. We explored associations between genetic variants in these genes and survival of nonsmall-cell lung cancer (NSCLC) patients by reanalyzing two datasets from published genome-wide association studies (GWASs). In the discovery by using the GWAS dataset of the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, we evaluated associations of 1,245 single-nucleotide polymorphisms (SNPs) in genes of four transporter families and two metabolic enzyme families with survival of 1,185 NSCLC patients. We then performed a replication analysis in the Harvard University Lung Cancer study (LCS) with 984 NSCLC patients. Multivariate Cox proportional hazards regression and false discovery rate (FDR) corrections were performed to evaluate the associations. We identified that 21 genotyped SNPs in eight gene regions were significantly associated with survival with FDR ≤0.1 in the discovery dataset. Subsequently, we confirmed six SNPs, which were putative functional, in ABCG1 of the ATP-binding cassette transporter family in the replication dataset. In the pooled analysis, two tagging (at r² > 0.8 for linkage disequilibrium with other replicated SNPs)/functional SNPs were independently associated with survival: rs225388 G > A [adjusted hazards ratio (HR)51.12, 95% confidence interval (CI)51.03-1.20, Ptrend = 4.6 3 10-3] and rs225390 A > G (adjusted HR51.16, 95% CI51.07-1.25, Ptrend = 3.8 3 10-4). Our results indicated that genetic variants of ABCG1 may be predictors of survival of NSCLC patients. [ABSTRACT FROM AUTHOR]

Alpinetin is a natural flavonoid abundantly present in the ginger family. Here, we investigated the effect of alpinetin on cholesterol efflux and lipid accumulation in oxidized low-density lipoprotein (ox-LDL)-treated THP-1 macrophages and human peripheral blood monocyte-derived macrophages (HMDMs). After exposing THP-1 macrophages to alpinetin, cholesterol efflux was determined by liquid scintillator. The mRNA and protein levels of peroxisome proliferator-activated receptor gamma (PPAR-γ ), liver X receptor alpha (LXR-α), ATP-binding cassette transporter A1 (ABCA1), and ABCG1 and scavenger receptor class B member 1 were determined by reverse-transcriptase PCR (RT-PCR) and Western blot analysis, respectively. Alpinetin promoted apolipoprotein A-I- and high-density-lipoprotein-mediated cholesterol efflux and elevated PPAR-γ and LXR-α mRNA and protein expression in a dose-dependent fashion in ox-LDL-treated THP-1 macrophages and HMDMs. Small interfering RNA-mediated silencing of PPAR-γ or LXR-α dose dependently reversed alpinetin-increased cholesterol efflux in THP-1 macrophages, indicating the involvement of PPAR-γ and LXR-α in alpinetin-promoted cholesterol efflux. Alpinetin inhibited ox-LDL-induced lipid accumulation and enhanced the expression of ABCA1 and ABCG1 mRNA and protein, which was reversed by specific knockdown of PPAR-γ or LXR-α. Taken together, our results reveal that alpinetin exhibits positive effects on cholesterol efflux and inhibits ox-LDL-induced lipid accumulation, which might be through PPAR-γ /LXR-α/ABCA1/ABCG1 pathway. [ABSTRACT FROM AUTHOR]

Atherosclerosis and accompanying cardiovascular disease are the first causes of mortality in patients undergoing maintenance hemodialysis. Anti-atherosclerotic effects of hemodiafiltration ( HDF) have been reported. Our study aimed to investigate the effect of serum derived from a healthy group ( n = 23), before and after hemodialysis ( HD) therapy ( n = 23), and before and after HDF therapy ( n = 17) on the expression of microRNA-33a and its target genes adenosine triphosphate-binding cassette transporter A1, G1 ( ABCA1, ABCG1) in THP-1 macrophages. Meanwhile, blood lipids and high-sensitivity C-reactive protein (hs- CRP) were measured in these groups. Our data showed that the expression of miRNA-33a was lower ( P < 0.05) and ABCA1 and ABCG1 were higher ( P < 0.05) in the healthy group than pre- HD and pre- HDF. miR-33a was significantly decreased ( P < 0.05) but ABCA1, ABCG1 was significantly increased ( P < 0.05) in post- HDF compared with pre- HDF, while these parameters in pre- and post- HD groups did not show any significant change ( P > 0.05). High density lipoprotein cholesterol ( HDL-C) was higher and hs- CRP was lower in the healthy group than pre- HD and pre- HDF groups. Moreover, a significant increase of HDL-C ( P < 0.05) and decrease ( P < 0.05) of hs- CRP was shown in post- HDF compared with pre- HDF, but HD appeared to have no significant change in these subjects. HDF therapy can downregulate miR-33a expression, and then result in ABCA1, ABCG1 upregulation and an increase in circulating HDL-C, leading to a possible anti-atherosclerosis effect to some extent. [ABSTRACT FROM AUTHOR]

Highlights: [•] Human ABCG1 was expressed in Saccharomyces cerevisiae BJ2168, affinity purified and reconstituted into liposomes. [•] ABCG1 ATPase activity was enhanced by resveratrol in cholesterol-poor membranes. [•] Resveratrol might interact with the membrane where this protein is immersed, thus modifying its activity. [Copyright &y& Elsevier]

High cholesterol turnover catalyzed by cholesterol 24-hydroxylase is essential for neural functions, especially learning. Because 24(S)-hydroxycholesterol (24- OHC), produced by 24-hydroxylase, induces apoptosis of neuronal cells, it is vital to eliminate it rapidly from cells. Here, using differentiated SH- SY5Y neuron-like cells as a model, we examined whether 24- OHC is actively eliminated via transporters induced by its accumulation. The expression of ABCA1 and ABCG1 was induced by 24- OHC, as well as TO901317 and retinoic acid, which are ligands of the nuclear receptors liver X receptor/retinoid X receptor ( LXR/ RXR). When the expression of ABCA1 and ABCG1 was induced, 24- OHC efflux was stimulated in the presence of high-density lipoprotein ( HDL), whereas apolipoprotein A-I was not an efficient acceptor. The efflux was suppressed by the addition of si RNA against ABCA1, but not by ABCG1 si RNA. To confirm the role of each transporter, we analyzed human embryonic kidney 293 cells stably expressing human ABCA1 or ABCG1; we clearly observed 24- OHC efflux in the presence of HDL, whereas efflux in the presence of apolipoprotein A-I was marginal. Furthermore, the treatment of primary cerebral neurons with LXR/ RXR ligands suppressed the toxicity of 24- OHC. These results suggest that ABCA1 actively eliminates 24- OHC in the presence of HDL as a lipid acceptor and protects neuronal cells. [ABSTRACT FROM AUTHOR]

Liver X-receptor (LXR) agonists have been postulated to enhance reverse cholesterol transport (RCT), a process believed to shuttle cholesterol from the periphery back to the liver. Enhancing RCT via the upregulation of cholesterol transporters such as the adenosine triphosphate-binding cassettes ABCA1 and ABCG1 could therefore inhibit the progression of atherosclerosis. LXR-623 is a synthetic ligand for LXRs α and β that has shown promise in animal models of atherosclerosis. The authors present results from a single ascending-dose study of the safety, pharmacokinetics, and pharmacodynamics of LXR-623 in healthy participants. LXR-623 was absorbed rapidly with peak concentrations (Cmax) achieved at approximately 2 hours. The Cmax and area under the concentration-time curve increased in a dose-proportional manner. The mean terminal disposition half-life was between 41 and 43 hours independently of dose. LXR activation resulted in a dose- dependent increase in ABCA1 and ABCG1 expression. The effect of LXR-623 concentration on ABCA1 and ABCG1 expression was further characterized via a population pharmacokinetic-pharmacodynamic analysis, yielding EC50 estimates of 526 ng/mL and 729 ng/mL, respectively. Central nervous system-related adverse events were observed at the 2 top doses tested. The pharmacodynamic effects described here are the first demonstration of "target engagement" by an LXR agonist in humans. [ABSTRACT FROM AUTHOR]

Liver X-receptor (LXR) agonists have been postulated to enhance reverse cholesterol transport (RCT), a process believed to shuttle cholesterol from the periphery back to the liver. Enhancing RCT via the upregulation of cholesterol transporters such as the adenosine triphosphate- binding cassettes ABCA1 and ABCG1 could therefore inhibit the progression of atherosclerosis. LXR-623 is a synthetic ligand for LXRs α and β that has shown promise in animal models of atherosclerosis. The authors present results from a single ascending-dose study of the safety, pharmacokinetics, and pharmacodynamics of LXR-623 in healthy participants. LXR-623 was absorbed rapidly with peak concentrations (Cmax) achieved at approximately 2 hours. The Cmax and area under the concentration-time curve increased in a dose-proportional manner. The mean terminal disposition half-life was between 41 and 43 hours independently of dose. LXR activation resulted in a dose-dependent increase in ABCA1 and ABCG1 expression. The effect of LXR-623 concentration on ABCA1 and ABCG1 expression was further characterized via a population pharmacokinetic-pharmacodynamic analysis, yielding EC50 estimates of 526 ng/mL and 729 ng/mL, respectively. Central nervous system-related adverse events were observed at the 2 top doses tested. The pharmacodynamic effects described here are the first demonstration of "target engagement" by an LXR agonist in humans. [ABSTRACT FROM AUTHOR]

Transporters in the ABCG family appear to be involved in the cellular excretion of cholesterol and other sterols in a cell- and tissue-specific fashion. Overexpression of ATP-binding cassette transporters G1 (Abcg1) and G4 (Abcg4) can promote cellular cholesterol efflux to high-density lipoprotein (HDL), but the in vivo functions of Abcg4 are poorly understood. We used mice with knockouts of Abcg1 or Abcg4 singly or together to further elucidate the function of these transporters. Abcg1 and Abcg4 are highly expressed in the brain and are found in both astrocytes and neurons. Whereas Abcg1-/- or Abcg4-/- mice showed essentially normal levels of brain sterols, in Abcg1-/-/Abcg4-/- mice, levels of several sterol intermediates in the cholesterol biosynthetic pathway, namely desmosterol, lathosterol, and lanosterol, as well as 27-OH cholesterol, were increased 2- to 3-fold. Overexpression of Abcg1 or Abcg4 promoted efflux of desmosterol and cholesterol from cells to HDL, and combined deficiency of these transporters led to defective efflux and accumulation of these sterols in primary astrocytes. Consistent with defective efflux and sterol accumulation, cholesterol biosynthesis was reduced in Abcg1-/-/Abcg4-/- astrocytes. The accumulation of desmosterol, a known liver-X receptor (LXR) activator, was associated with increased expression of LXR target genes, including ATP-binding cassette transporter A1, and increased apolipoprotein E secretion in Abcg1-/-/ Abcg4-/- astrocytes. Our findings provide the first in vivo demonstration of a role for Abcg4 in sterol efflux in the brain and show that Abcg1 and Abcg4 have overlapping functions in astrocytes, promoting efflux of cholesterol, desmosterol, and possibly other sterol biosynthetic intermediates to HDL. [ABSTRACT FROM AUTHOR]

Abstract: Oxysterols result from cholesterol by enzymatic or oxidative processes. Some exert cytotoxic effects leading to necrosis or apoptosis. Detoxification of these compounds mainly occurs in the liver and requires transport from peripheral tissues towards it. Some ATP-binding cassette transporters are involved in export of cytotoxic compounds. In the current study, we investigated whether ABC transporter family member G1 (ABCG1) may be involved in oxysterol transport, since its gene expression is highly responsive to oxysterol loading. TetOff HeLa cells stably expressing ABCG1 showed decreased mass uptake of 7β-hydroxycholesterol (7β-HC) whereas that of other physiologically relevant oxysterols was unaffected. Application of 7β-HC to ABCG1 expressing cells induced hyperpolarization of mitochondrial membrane potential and production of reactive oxygen species, indicating energy consumption by the ATP-binding cassette transporter when it is activated by its correct substrate. Our study points to detoxification as one of potential cellular functions of ABCG1. We assume that ABCG1 protects against 7β-HC-induced cell death, an important role in prevention of neurodegenerative and cardiovascular disease. [Copyright &y& Elsevier]

The release of cholesterol from choroid plexus epithelial cells (CPE) plays an important role in cholesterol homeostasis in the CSF. The purpose of this study was to clarify the molecules involved in cholesterol release in CPE and the regulation mechanisms of the cholesterol release by the liver X receptor (LXR) using a conditionally immortalized CPE line (TR-CSFB3). The mRNA expression of LXRα, LXRβ and their target genes, ATP-binding cassette transporter (ABC)A1, ABCG1, ABCG4 and ABCG5, were detected in rat choroid plexus. ABCA1 and ABCG1 protein were detected in the plasma membrane of TR-CSFB3 cells. Following treatment with 24 S-hydroxycholesterol, an endogenous LXR ligand, the expression of ABCA1 and ABCG1 were induced in TR-CSFB3 cells. Moreover, apolipoprotein (apo)AI- and high-density lipoprotein (HDL)-mediated cholesterol release to the apical side of TR-CSFB3 cells was facilitated by this treatment, whereas that to the basal side was not affected. Following 24 S-hydroxycholesterol treatment, apoE3-dependent cholesterol release from TR-CSFB3 cells was enhanced more than the apoE4-dependent release. These results suggest that LXR activation facilitates cholesterol release into the CSF from CPE through the functional induction of ABCA1 and ABCG1. The difference between apoE3 and apoE4 suggests that the cholesterol release from CPE is related to the development of neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Abstract: The ATP-binding cassette transporter ABCG1 mediates the transport of excess cholesterol from macrophages and other cell types to high density lipoprotein (HDL) but not to lipid-depleted apolipoprotein AI. Several splice variants which may have different functions have been identified in mammals. In the current study, we characterized the human splice variant ABCG1(666), which differs from full-length ABCG1(678) by absence of an internal segment of 12 amino acids (VKQTKRLKGLRK). Accordingly spliced ABCG1 transcripts were detected in macrophages and liver in approximately twofold higher amounts than the alternatively spliced ABCG1 form encoding full-length ABCG1. We used transient and stable expression of ABCG1(666) fusion proteins to characterize glycosylation, subcellular localization, molecular interaction and functions of this ABCG1 variant. It could be demonstrated that ABCG1(666) is located at the cell surface and has the ability to form cholesterol transport competent homodimers which affect cellular cholesterol export in a similar manner as previously characterized forms of ABCG1. Our results support that ABCG1(666) may in fact be the most prominent form of functional ABCG1 expressed in the human. [Copyright &y& Elsevier]

Background: Cholesterol efflux from cells to apolipoprotein A-I (apoA-I) acceptors via the ATP-binding cassette transporters ABCA1 and ABCG1 is thought to be central in the antiatherogenic mechanism. MicroRNA (miR)-33 is known to target ABCA1 and ABCG1 in vivo., Methods and Results: We assessed the impact of the genetic loss of miR-33 in a mouse model of atherosclerosis. MiR-33 and apoE double-knockout mice (miR-33(-/-)Apoe(-/-)) showed an increase in circulating HDL-C levels with enhanced cholesterol efflux capacity compared with miR-33(+/+)Apoe(-/-) mice. Peritoneal macrophages from miR-33(-/-)Apoe(-/-) mice showed enhanced cholesterol efflux to apoA-I and HDL-C compared with miR-33(+/+)Apoe(-/-) macrophages. Consistent with these results, miR-33(-/-)Apoe(-/-) mice showed reductions in plaque size and lipid content. To elucidate the roles of miR-33 in blood cells, bone marrow transplantation was performed in these mice. Mice transplanted with miR-33(-/-)Apoe(-/-) bone marrow showed a significant reduction in lipid content in atherosclerotic plaque compared with mice transplanted with miR-33(+/+)Apoe(-/-) bone marrow, without an elevation of HDL-C. Some of the validated targets of miR-33 such as RIP140 (NRIP1) and CROT were upregulated in miR-33(-/-)Apoe(-/-) mice compared with miR-33(+/+)Apoe(-/-) mice, whereas CPT1a and AMPKα were not., Conclusions: These data demonstrate that miR-33 deficiency serves to raise HDL-C, increase cholesterol efflux from macrophages via ABCA1 and ABCG1, and prevent the progression of atherosclerosis. Many genes are altered in miR-33-deficient mice, and detailed experiments are required to establish miR-33 targeting therapy in humans.