OBJECTIVETo study the effects of high-density lipoprotein (HDL) and oxidized high-density lipoprotein (ox-HDL) on the expression of ATP-binding cassette transporter A1 (ABCAl) and cholesterol efflux in human umbilical vein endothelial cells (HUVECs).

METHODSIn vitro cultured HUVECs were incubated in the presence of 100 microg/ml HDL or 100 microg/ml ox-HDL for 24 h, using PBS as the negative control. ABCA1 mRNA level and cholesterol efflux rate were determined using RT-PCR and a liquid scintillator, respectively.

RESULTSHDL and ox-HDL significantly elevated the level of ABCA1 mRNA by 58% and 23% relative to the control level, respectively (P<0.05). The cholesterol efflux rate in ox-HDL group was significantly lower than that in HDL group (P<0.01).

CONCLUSIONHDL increases ABCAl expression and cholesterol efflux in HUVECs. Oxidative modification of HDL decrease cholesterol efflux by inhibiting the expression of ABCAl, suggesting a possible mechanism of ox-HDL in the pathogenesis of atherosclerosis.

ATP Binding Cassette Transporter 1 ; ATP-Binding Cassette Transporters ; genetics ; metabolism ; Cells, Cultured ; Cholesterol ; metabolism ; Endothelial Cells ; metabolism ; Humans ; Lipoproteins, HDL ; metabolism ; physiology ; Umbilical Veins ; cytology

The formation of macrophage-derived foam cells is a typical feature of atherosclerosis (AS). Reverse cholesterol efflux (RCT) is one of important factors for the formation of macrophage foam cells. In this study, macrophage form cells were induced by oxidized low density lipoprotein (ox-LDL) and then treated with different concentrations of ferulic acid, so as to observe the effect of ferulic acid on the intracellular lipid metabolism in the ox-LDL-induced macrophage foam cell formation, the cholesterol efflux and the mRNA expression and protein levels of ATP binding cassette transporter A1 (ABCA1) and ATP binding cassette transporter G1 (ABCG1) that mediate cholesterol efflux, and discuss the potential mechanism of ferulic acid in resisting AS. According to the findings, compared with the control group, the ox-LDL-treated group showed significant increase in intracellular lipid content, especially for the cholesterol content; whereas the intracellular lipid accumulation markedly decreased, after the treatment with ferulic acid. The data also demonstrated that the mRNA and protein expressions of ABCA1 and ABCG1 significantly increased after macrophage foam cells were treated with different concentrations of ferulic acid. In summary, ferulic acid may show the anti-atherosclerosis effect by increasing the surface ABCA1 and ABCG1 expressions of macrophage form cells and promoting cholesterol efflux.
ATP Binding Cassette Transporter 1 ; analysis ; genetics ; ATP Binding Cassette Transporter, Sub-Family G, Member 1 ; ATP-Binding Cassette Transporters ; analysis ; genetics ; Animals ; Cells, Cultured ; Cholesterol ; metabolism ; Coumaric Acids ; pharmacology ; Foam Cells ; drug effects ; metabolism ; Lipoproteins ; analysis ; genetics ; Mice

Liver is regarded as one of the most important organs for drug clearance in the body, which mediates both the metabolism and biliary excretion of drugs. Transporters are a class of functional membrane proteins and control the movement of substances into or out of cells. Transporters, which are extensively expressed in the liver, play important roles in the drug hepatic disposition by regulating the uptake of drugs from blood into hepatocytes or the efflux of drugs and their metabolites into bile. In this review, the localization, functions and substrate selectivity of the major transporters in the liver will be summarized, and the impacts of these transporters on drug hepatic disposition, the potential drug-drug interactions as well as their genetic polymorphisms will also be reviewed.
ATP Binding Cassette Transporter, Sub-Family G, Member 2 ; ATP-Binding Cassette Transporters ; genetics ; metabolism ; ATP-Binding Cassette, Sub-Family B, Member 1 ; genetics ; metabolism ; Bile ; metabolism ; Biological Transport ; Drug Interactions ; Humans ; Liver ; metabolism ; Membrane Transport Proteins ; genetics ; metabolism ; Metabolic Clearance Rate ; Multidrug Resistance-Associated Proteins ; genetics ; metabolism ; Neoplasm Proteins ; genetics ; metabolism ; Organic Anion Transporters ; genetics ; metabolism ; Organic Anion Transporters, Sodium-Dependent ; metabolism ; Organic Anion Transporters, Sodium-Independent ; genetics ; metabolism ; Organic Cation Transport Proteins ; genetics ; metabolism ; Pharmacokinetics ; Polymorphism, Genetic ; Symporters ; metabolism

OBJECTIVETo investigate the association between polymorphisms at -14 bp and zinc finger protein(ZNF) sites of ATP-binding cassette transporter A1 (ABCA1) gene promotor and high density lipoprotein-cholesterol (HDL-C) level and coronary heart disease (CHD).

METHODSPolymorphisms of Bme13901 restriction site at -14 bp and an insertion/deletion site of ACCCC in variable number of tandem repeats-zinc finger protein(VNTR-ZNF) of ABCA1 gene were detected using PCR in 260 CHD patients and 220 healthy subjects from a Chinese population in Tianjin.

RESULTSCT genotype was most common in both groups with no differences found in between (P> 0.05). No differences were found in the frequencies of the rare T allele for -14 bp (P> 0.05). For the -14 bp site, subjects with CT/TT genotype had a lower serum mean concentration of HDL-C compared with those with the CC genotype (P< 0.05). Genotypic frequencies of VNTR-ZNF were 6.2% for the inserted form, 43.8% for the deleted form and 50.0% for the inserted/deleted form. No significant difference was found in the distribution of allele and genotype, or in the levels of HDL-C between the two groups (P> 0.05).

CONCLUSIONThe genotypes at -14 bp of ABCA1 gene are associated with the plasma level of HDL-C. HDL-C levels in T allele carriers were significantly lower (P< 0.05). No association was found between variations in ABCA1 VNTR-ZNF and plasma levels of HDL-C, or between the ABCA1 -14 bp and VNTR-ZNF polymorphisms and susceptibility for CHD.

ATP Binding Cassette Transporter 1 ; ATP-Binding Cassette Transporters ; genetics ; Cardiovascular Diseases ; genetics ; metabolism ; Case-Control Studies ; Cholesterol, HDL ; genetics ; metabolism ; DNA-Binding Proteins ; genetics ; Female ; Humans ; Male ; Middle Aged ; Polymorphism, Genetic ; Promoter Regions, Genetic

OBJECTIVETo study the effect of peroxisome proliferators activated receptors (PPAR) alpha, gamma ligand on ATP-binding cassette transporter A1 (ABCA1) and caveolin-1 expressions and cholesterol, ox-LDL contents in human monocyte derived foam cells.

METHODMalondialdehyde (MDA) was measured by TBARS method, ox-LDL detected by ELISA method, cholesterol measured by fluorescence spectrophotometric method, ABCA1, caveolin-1 mRNA and protein expressions determined by RT-PCR and Western blot, in human monocytes, foam cells [human monocyte-derived macrophage induced by myristate acetate (PMA) further treated with 50 mg/L ox-LDL for 24 h], foam cells plus 10 micromol/L pioglitazone for 48 h, foam cells plus 5 micromol/L clofibrate for 48 h.

RESULTThe intracellular total cholesterol (TC), free cholesterol (FC), cholesteryl ester (CE), ox-LDL and lipid peroxide were significantly increased and the membrane expressions of ABCA1, caveolin-1 were down-regulated in foam cells compared to monocytes (all P < 0.05) and these changes were significantly attenuated by cotreatment with PPARalpha, gamma ligand.

CONCLUSIONThe anti-atherosclerosis effects of PPARalpha, gamma ligand are related to reducing cholesterol contents and up-regulating ABCA1, caveolin-1 expressions in foam cells.

ATP Binding Cassette Transporter 1 ; ATP-Binding Cassette Transporters ; metabolism ; Caveolin 1 ; metabolism ; Cell Line ; Cholesterol ; genetics ; metabolism ; Foam Cells ; metabolism ; Gene Expression ; Humans ; Malondialdehyde ; metabolism ; Monocytes ; metabolism ; PPAR alpha ; metabolism ; PPAR gamma ; metabolism

Pulmonary surfactant (PS) is synthesized and secreted by alveolar epithelial type II (AEII) cells, which is a complex compound formed by proteins and lipids. Surfactant participates in a range of physiological processes such as reducing the surface tension, keeping the balance of alveolar fluid, maintaining normal alveolar morphology and conducting host defense. Genetic disorders of the surfactant homeostasis genes may result in lack of surfactant or cytotoxicity, and lead to multiple lung diseases in neonates, children and adults, including neonatal respiratory distress syndrome, interstitial pneumonia, pulmonary alveolar proteinosis, and pulmonary fibrosis. This paper has provided a review for the functions and processes of pulmonary surfactant metabolism, as well as the connection between disorders of surfactant homeostasis genes and lung diseases.
ATP-Binding Cassette Transporters ; genetics ; DNA-Binding Proteins ; genetics ; Homeostasis ; Humans ; Lung Diseases ; genetics ; Pulmonary Surfactant-Associated Protein C ; genetics ; Pulmonary Surfactants ; metabolism ; Transcription Factors

ATP Binding Cassette Transporter 1 ; ATP-Binding Cassette Transporters ; genetics ; metabolism ; Anticholesteremic Agents ; pharmacology ; Cell Line ; Drug Synergism ; Humans ; Macrophages ; cytology ; metabolism ; PPAR gamma ; metabolism ; Pravastatin ; pharmacology ; RNA, Messenger ; genetics ; metabolism ; Thiazolidinediones ; pharmacology ; Up-Regulation ; drug effects

OBJECTIVETo study the influence and mechanism of HBV core region mutation on HLA-I expression.

METHODSEukaryotic expression vectors of HBV core region mutations L97, G87 and V60 were constructed and transfected into HepG2 cells. Then the expressions of HLA-I were detected by RT-PCR and Western blot. The mRNA of antigen-presentation-associated genes, including LMP2, TAP1 and tapasin, were measured using RT-PCR.

RESULTSDifferent levels of HBsAg in the supernatants of transfected cells were detected by ELISA. The HBsAg of the mutated groups was markedly higher than that of the wild ones. All the transfected cells expressed HLA-I molecules, especially the L97 group. It was also found that the mRNA of TAP1 gene was up-regulated, while the mRNA of LMP and tapasin genes had no changes.

CONCLUSIONThe core region mutation of HBV can lower the expression of HBsAg; mutated groups and wild ones both can increase the expression of HLA-I molecules. The up-regulation of TAP1 gene expression might be the cause of these changes.

ATP-Binding Cassette Sub-Family B Member 2 ; ATP-Binding Cassette Transporters ; metabolism ; Gene Expression Regulation, Viral ; Hep G2 Cells ; Hepatitis B Surface Antigens ; metabolism ; Hepatitis B virus ; genetics ; Histocompatibility Antigens Class I ; genetics ; metabolism ; Humans ; Mutation

Drug transport is an important source of inter-individual variations in drug responses and is also a common site where drug-drug interactions happen. In recent years, more and more novel identified transporters have been added into the transporter super family, and this trend will continue in the future. Among the transporter members of this family, ATP-dependent efflux transporter P-glycoprotein (MDR1) and organic anion transporters (OATP) are the most important proteins involved in drug transport. MDR1 is the most well known transporter. Widely distributed in tissues such as the gastrointestinal tract, liver, kidney and so on, MDR1 plays an important role in drug absorption, distribution and excretion. Its functional genetic polymorphisms have significantly changed the pharmacokinetics of its substrate drugs, which has important clinical implications. OATP expressed in multiple tissues, and it mediated the drug excretion through the bile acid and kidney. Some genetic polymorphism of OATP genes is the cause of some abnormal drug responses.
ATP Binding Cassette Transporter, Subfamily B, Member 1 ; genetics ; Drug Interactions ; genetics ; Humans ; Membrane Transport Proteins ; genetics ; metabolism ; Organic Anion Transporters ; genetics ; Pharmaceutical Preparations ; metabolism ; Polymorphism, Genetic

OBJECTIVETo make prenatal dignosis of X-linked adrenoleukodystrophy (ALD) for the prevention of the disease.

METHODSEighteen amniocenteses were performed on 17 suspected carriers of X-ALD during 18-30 gestation weeks. The very long chain fatty acids (VLCFAs) levels of cultured amniocytes were tested by gas chromatography-mass spectrometry (GC/MS). The plasma VLCFAs levels were measured in 8 of the 18 prenatal diagnosed children when they were born or after abortion. ABCD1 gene mutation analysis was carried out in 8 cases by PCR and sequencing. ALDP of amniocytes was tested by Western blotting in 2 cases from a family, one female, another male, and the VLCFAs of cultured amniocytes were increased in both of them.

RESULTSAmong the 18 fetuses, 10 were males and 8 were females. The VLCFAs levels of the cultured amniocytes were increased in 3 males and 4 females. The postnatal plasma VLCFAs were normal in 5 cases with normal VLCFAs levels of amniocytes, and increased in 3 cases with high VLCFAs levels of amniocytes. ABCD1 gene mutations were found in 4 cases with high VLCFAs levels of amniocytes, no mutation was found in other 4 cases with normal VLCFAs levels of amniocytes. ALDP of amniocytes could be detected in the female with high VLCFAs levels of amniocytes, and it could not be detected in the male with high VLCFAs levels of amniocytes. Three male fetuses with high VLCFAs levels of amniocytes were aborted. The others who were born were normal clinically so far.

CONCLUSIONThe prenatal diagnosis is very important for the prevention of ALD. Amniocyte VLCFAs level analysis combined with ABCD1 gene mutation analysis and ALDP test could make a proper prenatal diagnosis.

ATP Binding Cassette Transporter, Sub-Family D, Member 1 ; ATP-Binding Cassette Transporters ; genetics ; Adrenoleukodystrophy ; diagnosis ; genetics ; metabolism ; Adult ; DNA Mutational Analysis ; Fatty Acids ; metabolism ; Female ; Gas Chromatography-Mass Spectrometry ; Humans ; Infant, Newborn ; Male ; Pregnancy ; Prenatal Diagnosis ; methods