ATP-binding Cassette Subfamily A Research Articles

The Role of ATP-Binding Cassette Subfamily A in Colorectal Cancer Progression and Resistance.

Colorectal cancer (CRC) is one of the most common malignancies worldwide; it is the fourth leading cause of cancer-related deaths. CRC arises due to mutations that can affect oncogenes, tumour suppressor genes and DNA repair genes. The lack of novel diagnostic and therapeutic targets and the development of chemoresistance are some of the major issues when dealing with CRC. The overexpression of ATP-binding cassette (ABC) transporters is considered one facilitating mechanism for chemoresistance. Furthermore, ABC transporters have additional roles in cancer development beyond multidrug resistance. In CRC, lipid dysregulation has a key role in tumour development and progression, as cancer cells rely on lipids for energy and rapid cell proliferation. ABC subfamily A (ABCA) contains the largest members of ABC proteins, mainly known for their role in lipid transport, mostly membrane lipids such as cholesterol and phospholipids. Although the exact mechanism of action of these members is not confirmed, their expression is usually correlated with tumour progression and therapy resistance, probably due to their role in lipid homeostasis. CRC shows alteration in the expression of ABCA transporters, which is usually linked to poor prognosis and overall survival. Therefore, as lipid transporters, their role in CRC is investigated, and their diagnostic and prognostic potential is evaluated. This minireview presents evidence from various studies suggesting that ABCA transporters might have an active role in CRC and can be utilized as potential diagnostic and therapeutic targets.

Recombinant Humanized IgG1 Antibody Promotes Reverse Cholesterol Transport through FcRn-ERK1/2-PPARα Pathway in Hepatocytes

Hyperlipidemia-associated lipid disorders are considered the cause of atherosclerotic cardiovascular disease. Reverse cholesterol transport (RCT) is a mechanism by which excess peripheral cholesterol is transported to the liver and further converted into bile acid for excretion from the body in feces, which contributes to reducing hyperlipidemia as well as cardiovascular disease. We previously found that the recombinant humanized IgG1 antibody promotes macrophages to engulf lipids and increases cholesterol efflux to high-density lipoprotein (HDL) through ATP-binding cassette sub-family A1 (ABCA1), one of the key proteins related to RCT. In the present study, we explored other RCT related proteins expression on hepatocytes, including scavenger receptor class B type I (SR-BI), apolipoprotein A-I (ApoA-I), and apolipoprotein A-II (ApoA-II), and its modulation mechanism involved. We confirmed that the recombinant humanized IgG1 antibody selectively activated ERK1/2 to upregulate SR-BI, ApoA-I, and ApoA-II expression in mice liver and human hepatocellular carcinoma cell lines HepG2 cells. The rate-limiting enzymes of bile acid synthesis, including cholesterol 7α-hydroxylase (CYP7A1) and sterol 27-hydroxylase (CYP27A1), exhibited a significant increase when treated with the recombinant humanized IgG1 antibody, as well as increased excretion of bile acids in feces. Besides, abolishment or mutation of peroxisome proliferator-activated receptor α (PPARα)/RXR binding site on SR-BI promoter eliminated SR-BI reporter gene luciferase activity even in the presence of the recombinant humanized IgG1 antibody. Knock down the neonatal Fc receptor (FcRn) on hepatocytes impaired the effect of recombinant humanized IgG1 antibody on activation of ERK1/2, as well as upregulation of SR-BI, ApoA-I, and ApoA-II expression. In conclusion, one of the mechanisms on the recombinant humanized IgG1 antibody attenuates hyperlipidemia in ApoE-/- mice model fed with high-fat-diet might be through reinforcement of liver RCT function in an FcRn-ERK1/2-PPARα dependent manner.

ATP-binding cassette transporter expression is widely dysregulated in frontotemporal dementia with TDP-43 inclusions.

The human brain is highly enriched in lipids and increasing evidence indicates that dysregulation of lipids in the brain is associated with neurodegeneration. ATP-binding cassette subfamily A (ABCA) transporters control the movement of lipids across cellular membranes and are implicated in a number of neurodegenerative diseases. However, very little is known about the role of ABCA transporters in frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP), which is a common form of younger-onset dementia. We therefore undertook a comprehensive analysis of the expression of ABCA transporters (ABCA1-13) in five key brain regions (amygdala, inferior temporal cortex, superior frontal cortex, cerebellum and parietal cortex) in FTLD-TDP and controls. We found that the expression of ABCA2, ABCA3, ABCA4, ABCA7, ABCA9, ABCA10 and ABCA13 was significantly altered in FTLD-TDP in a region-specific manner. In addition, the expression of ABCA transporters correlated specifically to different neural markers and TARDBP. These results suggest substantial dysregulation of ABCA transporters and lipid metabolism in FTLD-TDP and these changes are associated with neuroinflammation.

Comprehensive Analysis of ABCA Family Members in Lung Adenocarcinoma with Prognostic Values

ATP-binding cassette subfamily A (ABCA) has received wide recognition because it possesses the capacity to translocate its derivatives, xenobiotics, vitamins, and cholesterol across biological membranes. Some ABCA members have causative relevance to inborn diseases, and a number of studies have explored their functions in cancer progression and metastasis. Here, we explored the interrelation between ABCA genes and lung adenocarcinoma (LUAD). We specified the expression and functions of ABCA members in LUAD using the GEPIA, GEO, Human Protein Atlas, UALCAN, TIMER, and Kaplan-Meier Plotter databases. ABCA5, ABCA6, ABCA8, ABCA9, and ABCA10 were found to be significantly less expressed in LUAD and correlated with TP53 mutation in patients with LUAD. Furthermore, ABCA5, ABCA6, and ABCA8 were relevant to overall survival of patients with LUAD. In conclusion, this study showed that ABCA members may be related to the TP53 mutation of LUAD. Moreover, it may serve as a potential marker for the prognosis of LUAD.

Structural basis of substrate recognition and translocation by human ABCA4

Human ATP-binding cassette (ABC) subfamily A (ABCA) transporters mediate the transport of various lipid compounds across the membrane. Mutations in human ABCA transporters have been described to cause severe hereditary disorders associated with impaired lipid transport. However, little is known about the mechanistic details of substrate recognition and translocation by ABCA transporters. Here, we present three cryo-EM structures of human ABCA4, a retina-specific ABCA transporter, in distinct functional states at resolutions of 3.3–3.4 Å. In the nucleotide-free state, the two transmembrane domains (TMDs) exhibit a lateral-opening conformation, allowing the lateral entry of substrate from the lipid bilayer. The N-retinylidene-phosphatidylethanolamine (NRPE), the physiological lipid substrate of ABCA4, is sandwiched between the two TMDs in the luminal leaflet and is further stabilized by an extended loop from extracellular domain 1. In the ATP-bound state, the two TMDs display a closed conformation, which precludes the substrate binding. Our study provides a molecular basis to understand the mechanism of ABCA4-mediated NRPE recognition and translocation, and suggests a common ‘lateral access and extrusion’ mechanism for ABCA-mediated lipid transport.

Coffee prevents fatty liver disease induced by a high-fat diet by modulating pathways of the gut-liver axis.

Coffee consumption is inversely associated with the risk of non-alcoholic fatty liver disease (NAFLD). A gap in the literature still exists concerning the intestinal mechanisms that are involved in the protective effect of coffee consumption towards NAFLD. In this study, twenty-four C57BL/6J mice were divided into three groups each receiving a standard diet, a high-fat diet (HFD) or an HFD plus decaffeinated coffee (HFD+COFFEE) for 12 weeks. Coffee supplementation reduced HFD-induced liver macrovesicular steatosis (P<0·01) and serum cholesterol (P<0·001), alanine aminotransferase and glucose (P<0·05). Accordingly, liver PPAR- α (P<0·05) and acyl-CoA oxidase-1 (P<0·05) as well as duodenal ATP-binding cassette (ABC) subfamily A1 (ABCA1) and subfamily G1 (ABCG1) (P<0·05) mRNA expressions increased with coffee consumption. Compared with HFD animals, HFD+COFFEE mice had more undigested lipids in the caecal content and higher free fatty acid receptor-1 mRNA expression in the duodenum and colon. Furthermore, they showed an up-regulation of duodenal and colonic zonulin-1 (P<0·05), duodenal claudin (P<0·05) and duodenal peptide YY (P<0·05) mRNA as well as a higher abundance of Alcaligenaceae in the faeces (P<0·05). HFD+COFFEE mice had an energy intake comparable with HFD-fed mice but starting from the eighth intervention week they gained significantly less weight over time. Data altogether showed that coffee supplementation prevented HFD-induced NAFLD in mice by reducing hepatic fat deposition and metabolic derangement through modification of pathways underpinning liver fat oxidation, intestinal cholesterol efflux, energy metabolism and gut permeability. The hepatic and metabolic benefits induced by coffee were accompanied by changes in the gut microbiota.

MicroRNA‐146a Deficiency Promotes Atherosclerosis by Dysregulating Cholesterol Homeostasis in Macrophages

Atherosclerosis is a chronic inflammatory disease that results from imbalance of high‐density lipoprotein (HDL) cholesterol metabolism and a maladaptive immune response driven by the accumulation of cholesterol‐laden macrophages in the artery wall. MicroRNA‐146a (miR‐146a) serves as anti‐inflammatory function in a variety of cell types, but the underlying mechanisms of miR‐146a in atherosclerosis still remain unclear. In the present study, we assessed the impact of the genetic deficiency of miR‐146a in a mouse model of atherosclerosis and determined the miR‐146a‐mediated balance of cholesterol metabolism in macrophages. In comparison with miR‐146a+/+ApoE−/− mice fed with high‐cholesterol diet for 10 weeks, miR‐146a−/−ApoE−/− mice showed an increase number and area of atherosclerotic plaques, lipid content, pro‐inflammatory cytokines and abundant macrophages accumulated in the plaques. In addition, miR‐146a−/−ApoE−/− mice also showed decrease in HDL levels. Bone marrow chimera experiments indicated a major effect of miR‐146a deficiency on lesional macrophages. Bone marrow derived‐macrophages (BMDMs) were isolated from miR‐146a−/−ApoE−/− and miR‐146a+/+ApoE−/− mice to stimulated with oxidized low‐density lipoprotein (oxLDL). In comparison with BMDMs of miR‐146a+/+ApoE−/−, BMDMs of miR‐146a−/−ApoE−/− showed a significant oxLDL uptake and reduction in cholesterol efflux capacity. The expression of cholesterol transporters, including the ATP‐binding cassette sub‐family A1 (ABCA1) and sub‐family G1 (ABCG1) were significantly decreased in BMDMs of miR‐146a−/−ApoE−/−. By using the global gene expression analysis and argonaute‐2 immunoprecipitation, we demonstrated that toll‐like receptor 4 (TLR4) is directly targeted by miR‐146a. Overexpression of miR‐146a and silence of TLR4 not only increased the expression of ABCA1 and ABCG1, but also increased the cholesterol efflux capacity and reduced the oxidized LDL uptake. These data demonstrated that miR‐146a is involved in regulation of ABCA1 and ABCG1 by targeting TLR4, and that maintains the balance of HDL cholesterol metabolism to protect against the atherosclerosis. MiR‐146a is a potential target in treatment of atherosclerotic vascular disease.Support or Funding InformationMOST 104‐2321‐B‐400‐020‐MY3 (to L.‐J. C.) and MOST 104‐2321‐B‐400‐017 (to J.‐J. C.).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Decreased cholesterol uptake and increased liver x receptor-mediated cholesterol efflux pathways during prostaglandin F2 alpha-induced and spontaneous luteolysis in sheep.

In nonprimate species, it has been well established that prostaglandin F2 alpha (PGF2alpha) initiates luteolysis. Changes in intracellular cholesterol concentrations caused by modulation of cholesterol uptake and efflux may mediate PGF2alpha-induced luteolysis. These changes in cholesterol efflux and uptake are controlled, in part, by the liver x receptors (LXR) alpha (NR1H3) and beta (NR1H2), nuclear receptors that increase expression of genes necessary for cholesterol efflux or limiting cholesterol uptake. Therefore, we hypothesized that PGF2alpha reduces expression of cholesterol uptake and increases expression of cholesterol efflux genes, mediated in part by enhanced LXR activity. To test this hypothesis, an induced luteolysis model was used whereby ewes were treated during their midluteal phase with saline or PGF2alpha and corpora lutea (CL) collected 12, 24, or 48 h later for determination of mRNA and protein concentrations by quantitative real-time PCR and Western blot analysis, respectively. As a complementary approach, CL undergoing spontaneous luteolysis were compared to midluteal phase CL. The lipoprotein receptors responsible for cholesterol uptake were significantly decreased in both luteolysis models. Expression of the LXR target gene ATP binding cassette subfamily A1 (ABCA1), an important mediator of cholesterol efflux, was significantly increased in both experimental models. Chromatin immunoprecipitation confirmed that PGF2alpha treatment resulted in enhanced NR1H3 and NR1H2 binding to the ABCA1 promoter. Qualitative changes in lipid droplet distribution were also observed following PGF2alpha treatment. These data support the hypothesis that reduced cholesterol uptake and increased efflux mediate luteolysis in sheep, which is partially controlled by PGF2alpha stimulation of LXR activity.

Chrysin inhibits foam cell formation through promoting cholesterol efflux from RAW264.7 macrophages

Context: Chrysin, a natural flavonoid, has been shown to possess multiple pharmacological activities including anti-atherosclerosis.Objective: The effects of chrysin on foam cell formation and cholesterol flow in RAW264.7 macrophages were investigated in this work to explore the potential mechanism underlying its anti-atherogenic activity.Materials and methods: The inhibitive effect of chrysin on foam cell formation and cholesterol accumulation induced by oxidized low-density lipoprotein cholesterol (ox-LDL) was assessed by oil red O staining and intracellular total cholesterol and triglyceride quantification in RAW264.7 macrophages. The action of chrysin on cholesterol efflux and influx was tested by fluorescent assays. Real-time quantitative PCR was used to quantify the relative expression of cholesterol flow-associated genes and luciferase assay was applied to test the transcription activity of peroxisome proliferator-activated receptor gamma (PPARγ).Results: Chrysin dose dependently inhibited the formation of foam cells and prevented the enhanced cholesterol accumulation by ox-LDL. Treatment with chrysin (10 μM) significantly enhanced cholesterol efflux and substantially inhibited cholesterol influx. Simultaneously, chrysin significantly increased the mRNA levels of PPARγ, liver X receptor alpha (LXRα), ATP-binding cassette, sub-family A1 (ABCA1), and sub-family G1 (ABCG1), decreased scavenger receptor A1 (SR-A1) and SR-A2, and increased the transcriptional activity of PPARγ.Discussion and conclusion: Chrysin is a new inhibitor of foam cell formation that may stimulate cholesterol flow. Up-regulation of the classical PPARγ–LXRα–ABCA1/ABCG1 pathway and down-regulation of SR-A1 and SR-A2 may participate in its suppressive effect on intracellular cholesterol accumulation.

ABCA5 regulates amyloid-β peptide production and is associated with Alzheimer's disease neuropathology.

Brain cholesterol homeostasis is regulated by a group of proteins called ATP-binding cassette subfamily A (ABCA) transporters. Certain ABCA transporters regulate amyloid-β protein precursor (AβPP) processing to generate amyloid-β peptides (Aβ) and are associated with an increased risk for late-onset Alzheimer's disease (AD). ABCA5 is a little-known member of the ABCA subfamily with no known function. In this study we undertook a comprehensive analysis of ABCA5 expression in the human and mouse brains. We explored the potential role of ABCA5 in AβPP processing associated with AD pathology. ABCA5 was differentially expressed in multiple regions of both human and mouse brains. It was strongly expressed in neurons with only weak expression in microglia, astrocytes, and oligodendrocytes. ABCA5 was able to stimulate cholesterol efflux in neurons. ABCA5 expression was specifically elevated in the hippocampus of AD brains. Using two in vitro cell systems we demonstrated that ABCA5 reduces Aβ production, both Aβ40 and Aβ42, without altering AβPP mRNA and protein levels, indicating that the decrease in the Aβ levels was due to changes in AβPP processing and not AβPP expression. This report represents the first extensive expression and functional study of ABCA5 in the human brain and our data suggest a plausible function of ABCA5 in the brain as a cholesterol transporter associated with Aβ generation, information that may offer a potential new target for controlling Aβ levels in the brain.

Germinated brown rice regulates hepatic cholesterol metabolism and cardiovascular disease risk in hypercholesterolaemic rats

White rice (WR) is the staple food for many people around the world, but it is linked to increased risk of cardiovascular diseases (CVDs). Brown rice (BR) and germinated brown rice (GBR) are conceived to be the healthier alternatives. The present study evaluated the effects of WR, BR and GBR in the dietary management of CVD. Diet-induced hypercholesterolaemic rats were fed with WR, BR and GBR, in comparison with normal, high-fat diet (HFD) and Simvastatin-treated rats. Weight, lipid profile, plasma oxidized low-density lipoprotein (ox-LDL) and F2-isoprostane were evaluated. GBR reduced weight gain and improved lipid parameters, ox-LDL and F2-isoprostane, partly through transcriptional regulation of hepatic lipoprotein lipase (LPL), peroxisome proliferator-activated receptor gamma (PPARγ), adiponectin, ATP-binding cassette, subfamily A (ABCA), and v-akt murine thymoma viral oncogene homologue 1and homologue 3 (AKT1 and AKT3). The results suggest GBR could ameliorate CVD risk by modulating lipid metabolism and oxidative stress.

ABCA8 stimulates sphingomyelin production in oligodendrocytes

Members of the ABCA (ATP-binding cassette subfamily A) family are characterized by their ability to transport lipids across cellular membranes and regulate lipid homoeostasis in the brain and peripheral tissues. ABCA8 is a little-known member of this subfamily that was originally cloned from human brain libraries and has no known function. In an effort to elucidate the role of ABCA8in the brain we first undertook a comprehensive analysis of its expression in the human brain. ABCA8 was differentially expressed in multiple regions of adult human brains with significantly higher expression in oligodendrocyte-enriched white matter regions compared with grey matter cortical regions. We then assessed the impact of ABCA8 on sphingomyelin production in oligodendrocyte and showed that ABCA8 was able to significantly stimulate both sphingomyelin synthase 1 expression and sphingomyelin production. Furthermore, ABCA8 expression in the prefrontal cortex across the human life span correlated strongly with age-associated myelination, and the myelinating gene p25α was significantly up-regulated with ABCA8. The present study represents the first extensive expression and functional study of ABCA8in the human brain and the results strongly suggest that ABCA8 regulates lipid metabolism in oligodendrocytes and potentially plays a role in myelin formation and maintenance.

Changes in Sphingomyelin Level Affect Alpha-Synuclein and ABCA5 Expression

The pathological hallmark of Parkinson's disease (PD) is the presence of aggregated α-synuclein associated with lipids. Substantial evidence now exists to indicate that α-synuclein binds and interacts with regions of membranes that are enriched in lipids (lipid rafts). Lipids are transported around the brain by a group of proteins called ATP-Binding Cassette subfamily A (ABCA) transporters and in recent years there has been mounting evidence indicating that ABCA transporters regulate a number of neurodegenerative disease processes. Only recently a genome-wide association study reported that ABCA5 was genetically associated with a reduced risk for PD. However, very little is known about the role of lipids and ABCA5 in the pathological process of PD. In this study we investigate the impact of the lipid-raft lipid sphingomyelin on α-synuclein and ABCA5 expression. We also investigate in which primary human brain cells ABCA5 is expressed and whether the expression of ABCA5 is altered in PD brain. When SK-N-SH neuronal cells were treated with sphingomyelin the expression of both α-synuclein and ABCA5 was significantly increased, indicating sphingomyelin as a potential substrate for the ABCA5 transporter. ABCA5 was strongly expressed in neurons and moderately in microglia, with only weak expression observed in astrocytes and oligodendrocytes. The expression of ABCA5 was significantly elevated in PD brains compared to age- and gender-matched control brains, possibly as a protective response to the disease. These data provide new evidence indicating that lipid is important for α-synuclein pathology in PD.

Adeno-associated Virus Serotype 8 ApoA-I Gene Transfer Reduces Progression of Atherosclerosis in ApoE-KO Mice: Comparison of Intramuscular and Intravenous Administration

Apolipoprotein A-I (ApoA-I)/high-density lipoprotein (HDL)-raising treatments are effective antiatherosclerotic strategies. We have compared the antiatherogenic effects of human ApoA-I (hApoA-I) overexpression by intraportal and intramuscular gene transfer in atherosclerotic ApoE-knockout mice. Atherosclerotic lesions were induced by atherogenic diet. After atherosclerosis induction, a group of animals was killed and served as atherosclerosis baseline-control group. The remaining animals were randomized into the following groups: (1) atherosclerosis-progression-control, (2) intraportal/vector administration, and (3) intramuscular/vector administration. Aortas and hearts were processed for atherosclerotic quantification by en face Sudan IV and Oil Red-O, respectively. Liver and muscle specimens were processed for protein/gene expression analysis. A sustained increase in hApoA-I/HDL plasma levels was observed in both transduced groups. hApoA-I overexpression abolished plaque progression versus progression-control group. hApoA-I overexpression significantly reduced lesion macrophage, feature indicative of plaque stabilization. Scavenger receptor class-B type I (SR-BI), but not ATP-binding cassette, sub-family A (ABCA), member 1 (ABCA-1), was significantly upregulated in treated groups versus progression-controls. The results of this study show a similar effect of hApoA-I/HDL overexpression on plaque progression/stabilization by 2 different routes of administration. Our results showing similar effects using either intramuscular administration and intraportal route of administration may have significant clinical implications, given the reduced medical risk to patient and cost of intramuscular injections.

ABC Transporters in Saccharomyces cerevisiae and Their Interactors: New Technology Advances the Biology of the ABCC (MRP) Subfamily

Members of the ATP-binding cassette (ABC) transporter superfamily exist in bacteria, fungi, plants, and animals and play key roles in the efflux of xenobiotic compounds, physiological substrates, and toxic intracellular metabolites. Based on sequence relatedness, mammalian ABC proteins have been divided into seven subfamilies, ABC subfamily A (ABCA) to ABCG. This review focuses on recent advances in our understanding of ABC transporters in the model organism Saccharomyces cerevisiae. We propose a revised unified nomenclature for the six yeast ABC subfamilies to reflect the current mammalian designations ABCA to ABCG. In addition, we specifically review the well-studied yeast ABCC subfamily (formerly designated the MRP/CFTR subfamily), which includes six members (Ycf1p, Bpt1p, Ybt1p/Bat1p, Nft1p, Vmr1p, and Yor1p). We focus on Ycf1p, the best-characterized yeast ABCC transporter. Ycf1p is located in the vacuolar membrane in yeast and functions in a manner analogous to that of the human multidrug resistance-related protein (MRP1, also called ABCC1), mediating the transport of glutathione-conjugated toxic compounds. We review what is known about Ycf1p substrates, trafficking, processing, posttranslational modifications, regulation, and interactors. Finally, we discuss a powerful new yeast two-hybrid technology called integrated membrane yeast two-hybrid (iMYTH) technology, which was designed to identify interactors of membrane proteins. iMYTH technology has successfully identified novel interactors of Ycf1p and promises to be an invaluable tool in future efforts to comprehensively define the yeast ABC interactome.

Age-Associated Decrease of High-Density Lipoprotein-Mediated Reverse Cholesterol Transport Activity

High-density lipoproteins (HDL) are considered atheroprotective in contrast to low-density lipoproteins (LDL), which are atherogenic in their oxidized form. A growing body of evidence suggests that HDL exert part of their antiatherogenic effect by counteracting LDL oxidation as well as their proinflammatory effect. However, a number of studies, carried over the past 30 years, have shown that cholesterol efflux plays a major role in the atheroprotective effects of HDL and cholesterol homeostasis. These studies have further identified the scavenger receptor type B-I (SR-BI), the adenosine triphosphate (ATP)-binding cassette transporters ATP-binding cassette subfamily A1 (ABCA1), ATP-binding cassette subfamily G1 (ABCG1) and ABCG4, the liver X receptor/retinoid X receptor (LXR/RXR) and peroxisome proliferator-activated receptorgamma(PPAR gamma) transcription factors, the HDL components apolipoprotein A-I (apoA-I), lecithin-cholesterol acyltransferase (LCAT), and phospholipids as additional mediators of cholesterol transport. Cholesterol efflux occurs via three independent pathways: (1) aqueous diffusion, (2) nonspecific efflux via SR-BI receptors, and (3) specific efflux via cholesterol-responsive members of the ABC superfamily. Whereas aqueous diffusion and scavenger receptor class B, type I (SR-BI)-mediated efflux transport free cholesterol to a wide variety of cholesterol acceptors (particles containing phospholipids, HDL, and lipidated apo-lipoproteins; LDL, etc), the ABCA1 pathway mediates the transport of cholesterol in a unidirectional manner, mainly to lipid-poor apoA-I. In contrast, the ABCG1 pathway is responsible for the transport of cholesterol to all the subfamily members of HDL. Although HDL-mediated cholesterol efflux is apoA-I-dependent, recent studies have suggested an involvement of the enzyme paraoxonase 1 (PON1). Cholesterol efflux is carried on by a number of factors such as genetic mutations, smoking, stress, and high-fat diets. It is attenuated with aging due to changes in the composition and structure of HDL, especially the phosphatidylcholine/sphingomyelin ratio, the fluidity of the phospholipidic layer, the concentration of apoA-I, and the activity of PON1. This review summarizes the findings that cholesterol homeostasis is disrupted with aging as a consequence of dysfunctional cholesterol efflux and the impairment of physiological functions.

Liver X receptor antagonist reduces lipid formation and increases glucose metabolism in myotubes from lean, obese and type 2 diabetic individuals

Liver X receptors (LXRs) play important roles in lipid and carbohydrate metabolism. The purpose of the present study was to evaluate effects of the endogenous LXR agonist 22-R-hydroxycholesterol (22-R-HC) and its stereoisomer 22-S-hydroxycholesterol (22-S-HC), in comparison with the synthetic agonist T0901317 on lipid and glucose metabolism in human skeletal muscle cells (myotubes). Myotubes established from lean and obese control volunteers and from obese type 2 diabetic volunteers were treated with LXR ligands for 4 days. Lipid and glucose metabolisms were studied with labelled precursors, and gene expression was analysed using real-time PCR. Treatment with T0901317 increased lipogenesis (de novo lipid synthesis) and lipid accumulation in myotubes, this increase being more pronounced in myotubes from type 2 diabetic volunteers than from lean volunteers. Furthermore, 22-S-HC efficiently counteracted the T0901317-induced enhancement of lipid formation. Moreover, synthesis of diacylglycerol, cholesteryl ester and free cholesterol from acetate was reduced below baseline by 22-S-HC, whereas glucose uptake and oxidation were increased. Both 22-S-HC and 22-R-HC, in contrast to T0901317, decreased the expression of genes involved in cholesterol synthesis, whereas only 22-R-HC, like T0901317, increased the expression of the gene encoding the reverse cholesterol transporter ATP-binding cassette subfamily A1 (ABCA1). T0901317-induced lipogenesis and lipid formation was more pronounced in myotubes from type 2 diabetic patients than from lean individuals. 22-S-HC counteracted these effects and reduced de novo lipogenesis below baseline, while glucose uptake and oxidation were increased.