Induction of Intestinal ATP-binding Cassette Transporters by a Phytosterol-derived Liver X Receptor Agonist

Kaneko, Emi; Matsuda, Morihiro; Yamada, Yukio; Tachibana, Yukio; Shimomura, Iichiro; Makishima, Makoto

doi:10.1074/jbc.m304153200

Cited by 174 publications

(126 citation statements)

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“…First, mutations in either ABCG5 or ABCG8 have identical clinical and biochemical sequelae (1). The two genes are located in a head-to-head orientation on chromosome 2, have similar tissue-and cell-specific patterns of expression, and are coordinately regulated (1,(12)(13)(14)(15)(16). These features are consistent with the two genes being expressed from a divergent promoter, a feature found in other genes encoding protein constituents of functional complexes (17)(18)(19).…”

supporting

confidence: 62%

Missense Mutations in ABCG5 and ABCG8 Disrupt Heterodimerization and Trafficking

Graf

Cohen

Hobbs

2004

Journal of Biological Chemistry

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Mutations in ABCG5 (G5) or ABCG8 (G8) cause sitosterolemia, an autosomal recessive disease characterized by sterol accumulation and premature atherosclerosis. G5 and G8 are ATP-binding cassette (ABC) half-transporters that must heterodimerize to move to the apical surface of cells. We examined the role of N-linked glycans in the formation of the G5/G8 heterodimer to gain insight into the determinants of folding and trafficking of these proteins. Site-directed mutagenesis revealed that two asparagine residues (Asn 585 and Asn 592 ) are glycosylated in G5 and that G8 has a single N-linked glycan attached to Asn 619 . N-Linked glycosylation of G8 was required for efficient trafficking of the G5/G8 heterodimer, but mutations that abolished glycosylation of G5 did not prevent trafficking of the heterodimer. Both G5 and G8 are bound by the lectin chaperone, calnexin, suggesting that the calnexin cycle may facilitate folding of the G5/G8 heterodimer. To determine the effects of 13 disease-causing missense mutations in G5 and G8 on formation and trafficking of the G5/G8 heterodimer, mutant forms of the half-transporters were expressed in CHO-K1 cells. All 13 mutations reduced trafficking of the G5/G8 heterodimer from the endoplasmic reticulum to the Golgi complex, and most prevented the formation of stable heterodimers between G5 and G8. We conclude that the majority of the molecular defects in G5 and G8 that cause sitosterolemia impair transport of the sterol transporter to the cell surface.Mutations in either ABCG5 (G5) or ABCG8 (G8) cause sitosterolemia, an autosomal recessive disorder characterized by the accumulation of both plant-derived (primarily sitosterol) and animal-derived sterols (cholesterol) in plasma and tissues (1-3). In mice, G5 and G8 are located on the apical surfaces of enterocytes and hepatocytes, where they limit the absorption of dietary sterols and promote the excretion of cholesterol into bile, respectively (4 -8). Individuals with sitosterolemia have a generalized increase in the absorption of dietary neutral sterols and a defect in the excretion of these sterols into bile (8 -10). This impairment in sterol trafficking results in the deposition of neutral sterols in the skin as xanthomas and in the walls of the coronary arteries, causing premature atherosclerosis.G5 and G8 are both glycoproteins (11). If G5 or G8 is expressed alone in cultured cells it is retained in the ER, 1 and its glycans remain sensitive to endoglycosidase H, an enzyme that removes immature, high mannose N-linked glycans that have not been processed to mature oligosaccharides in the Golgi complex. If both proteins are expressed in the same cell, the N-linked sugars become insensitive to endoglycosidase H and sensitive to neuraminidase, which cleaves sialic acid residues added in the trans-Golgi complex. As G5 and G8 transit from the ER to the cell surface, the changes in glycan structure result in an increase in the apparent molecular mass of each protein when analyzed by immunoblotting.ABC half-transporters must homodime...

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supporting

confidence: 62%

Missense Mutations in ABCG5 and ABCG8 Disrupt Heterodimerization and Trafficking

Graf

Cohen

Hobbs

2004

Journal of Biological Chemistry

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“…Modified PS and stanols have been shown to modify the cholesterol influx and efflux from cells by altering nuclear hormone receptor activity, although it is still under discussion whether such a direct effect on the gene level can be considered one of the key mechanisms of action of PS (Plat and Mensink, 2002;Kaneko et al, 2003;Plosch et al, 2004;Calpe-Berdiel et al, 2005). The potential effect on nuclear hormone receptors could also influence gene expression of inflammatory mediators such as iNOS, COX-2 and IL-6 (Joseph et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Dose-response effects of different plant sterol sources in fat spreads on serum lipids and C-reactive protein and on the kinetic behavior of serum plant sterols

et al. 2007

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Objective: To test the dose-response effect on low-density lipoprotein cholesterol (LDL-c) of plant sterols (PS) from different sources in a low-fat spread. Methods: Dose responses of soybean oil (BO), tall oil (TO) and a mix of tall oil and rapeseed oil (TO/RP) as fatty acid esters were tested in a parallel design in free-living subjects recruited from the general community who had elevated cholesterol concentrations. Subjects received either control for 6 weeks or 1.6 g PS per day for 3 weeks, then 3.0 g/day for 3 weeks. Results: LDL-c was lowered significantly by consumption of 1.6 g/day of PS (À10.4%, range À7.3 to À11.4%). Increasing the dose to 3.0 g/day modestly reduced LDL-c concentrations further to À14.7%. TO, containing 78% sitosterol, produced an increase in serum sitosterol of 6.5 nmol/ml, while BO, containing only 27% campesterol, produced an increase in serum campesterol of 9.5 nmol/ml in 6 weeks. After PS withdrawal, serum sterols declined by 50% within 2 weeks. Conclusion: Different PS sources were equally effective in lowering serum LDL-c concentrations. The decrease in absolute concentrations of LDL-c was dependent on the baseline concentrations. IntroductionA large number of human intervention studies have been performed using plant sterols (PS) or stanols incorporated into different food matrices to study their cholesterollowering effects. These studies are based on unesterified (free) or esterified PS or stanols, where the esterification is mostly based on vegetable-oil-derived fatty acids. Since the first publications of Mattson et al. in 1977 and1982, in which the efficacy of the ester format was shown, the interest in enriching foods with PS or stanol esters as an effective means of lowering total cholesterol (TC) and lowdensity lipoprotein-cholesterol (LDL-c) has increased. Quite a number of different food formats are now available, such as spreads, yogurts or milks, which can be taken on a daily basis. These foods formats typically provide between 1.5 and 2.5 g/day of PS or stanols from one or more servings, which have been proven to result in a 10-15% LDL-c lowering.From these studies considered collectively, the effective dose range can be established. It was stated in a recent metaanalysis of 41 studies that increasing the dose of PS or stanols to above 2.5 g/day results in little additional effects on lowering cholesterol (Katan et al., 2003). A few studies using specific PS sources and formats have also shown a dose response in smaller groups (Weststrate and Meijer, 1998;Hendriks et al., 1999). However, these studies were based on parallel groups or random assignment to the order of PS dose. One study has examined using PS the effect of four Correspondence: Dr PM Clifton, CSIRO Human Nutrition, Gate 13 Kintore Ave, Adelaide, SA 5000, Australia. E-mail: peter.clifton@csiro.au Guarantor: PM Clifton. Contributors: PMC and GSMJED designed the study; the intervention part was organized and monitored by PMC. PMC and MM coordinated the serum analysis. HCMvdK performed the data analysis ...

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“…Mammalian Two-hybrid Assay-Cells were transfected using calcium phosphate buffer as described (20). Cells were harvested, and luciferase and ␤-galactosidase activities were measured using a lumimometer (Molecular Devices).…”

Section: Methodsmentioning

confidence: 99%

Liver X Receptor β (LXRβ) Interacts Directly with ATP-binding Cassette A1 (ABCA1) to Promote High Density Lipoprotein Formation during Acute Cholesterol Accumulation

Hozoji-Inada

Munehira

Nagao

et al. 2011

Journal of Biological Chemistry

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Cells have evolved multiple mechanisms for maintaining cholesterol homeostasis, and, among these, ATP-binding cassette protein A1 (ABCA1)-mediated cholesterol efflux is highly regulated at the transcriptional level through the activity of the nuclear receptor liver X receptor (LXR). Here, we show that in addition to its well defined role in transcription, LXR␤ directly binds to the C-terminal region ( Disruption of cellular cholesterol homeostasis can lead to a variety of pathological conditions, including cardiovascular disease (1). ATP-binding cassette protein A1 (ABCA1), 2 an important regulator of cholesterol homeostasis, mediates the release of cellular excess free cholesterol and phospholipids to apolipoprotein A-I (apoA-I), an extracellular acceptor circulating in plasma, to form high density lipoprotein (HDL) (2-5). HDL formation is the only pathway through which excess cholesterol can be eliminated from nonhepatic cells. Defects in ABCA1 cause Tangier disease (6 -8), a condition in which patients have a near absence of circulating HDL, prominent cholesterol-ester accumulation in tissue macrophages, and premature atherosclerotic vascular disease (1, 9).The ABCA1-mediated release of cholesterol is highly regulated at the transcriptional level. When excess cholesterol accumulates in cells, intracellular concentrations of oxysterols increase and activate liver X receptor (LXR), which, in turn, stimulates ABCA1 gene transcription and increased expression of ABCA1 with associated elimination of excess cholesterol (10 -12). However, cholesterol is required for cell function and proliferation, and the intracellular cholesterol concentration must be maintained within a narrow range. Consequently, ABCA1-mediated cholesterol release is also regulated at the post-translational level. Several proteins, including syntrophins (13, 14), JAK2 (15), and LXR␤ (16), have been reported to interact with ABCA1 and modulate its degradation and function. However, the precise mechanism(s) by which ABCA1 activity is regulated post-translationally remains unclear.We previously reported (16) that a fraction of cytosolically localized LXR␤ may interact with ABCA1 on the plasma membrane and modulate the function of ABCA1. In WI-38 and THP-1 cells, endogenous LXR␤ interacts with ABCA1 under conditions in which LXR ligands do not accumulate, i.e. when cholesterol is not in excess. LXR␤ suppresses ABCA1-mediated cholesterol efflux. However, the mechanism by which LXR␤ suppresses ABCA1 functions was not clear. In this study, we identified two leucine residues in the C-terminal region of ABCA1 responsible for the interaction with LXR␤ and showed that LXR␤ interaction suppresses ATP binding to ABCA1 and thereby keeps ABCA1 standby on the plasma membrane for acute cholesterol accumulation. EXPERIMENTAL PROCEDURESMaterials-The LXR ligand TO901317, 22(R)-hydroxycholesterol, 25-hydroxycholesterol, and Alexa Fluor 546 succinimidyl esters were purchased from Cayman Co., Sigma, Stelaroids, and Molecular Probes, respectively. A cholesterol oxidas...

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Induction of Intestinal ATP-binding Cassette Transporters by a Phytosterol-derived Liver X Receptor Agonist

Abstract: The nuclear receptors liver X receptor (LXR)␣

Cited by 174 publications

References 44 publications

Missense Mutations in ABCG5 and ABCG8 Disrupt Heterodimerization and Trafficking

Missense Mutations in ABCG5 and ABCG8 Disrupt Heterodimerization and Trafficking

Dose-response effects of different plant sterol sources in fat spreads on serum lipids and C-reactive protein and on the kinetic behavior of serum plant sterols

Liver X Receptor β (LXRβ) Interacts Directly with ATP-binding Cassette A1 (ABCA1) to Promote High Density Lipoprotein Formation during Acute Cholesterol Accumulation

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