The Tangier disease gene product ABC1 controls the cellular apolipoprotein-mediated lipid removal pathway

Lawn, Richard M.; Wade, David P.; Garvin, Michael R.; Wang, Fudi; Schwartz, K.; Porter, Jonathan; Seilhamer, Jeffrey J.; Vaughan, Ashley M.; Oram, John F.

doi:10.1172/jci8119

Cited by 695 publications

(508 citation statements)

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“…The principal molecules involved in the efflux of cholesterol from macrophage foam cells are ABCA1 and ABCG1 [4,5] . ABCA1, the mutant molecule in Tangier disease, is involved in the efflux of cholesterol from peripheral tissue macrophages to lipid-free apolipoproteins, and in particular to apoAI [20][21][22] , whereas ABCG1 facilitates cellular cholesterol efflux from macrophages to lipidated particles such as mature HDL, but not to lipid-free apolipoproteins [23,24] . It has previously been reported that ibrolipim increased LPL mRNA levels, LPL protein mass, and LPL activity in post-heparin plasma and reduced plasma TG levels with concomitant increases of HDL-C levels in animals with lipid disorder.…”

Section: Discussionmentioning

confidence: 99%

Ibrolipim increases ABCA1/G1 expression by the LXRα signaling pathway in THP-1 macrophage-derived foam cells

et al. 2010

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Aim: To determine the effects and potential mechanisms of ibrolipim on ATP-binding membrane cassette transporter A-1 (ABCA1) and ATP-binding membrane cassette transporter G-1 (ABCG1) expression from human macrophage foam cells, which may play a critical role in atherogenesis. Methods: Human THP-1 cells pre-incubated with ox-LDL served as foam cell models. Specific mRNA was quantified using real-time RT-PCR and protein expression using Western blotting. Cellular cholesterol handling was studied using cholesterol efflux experiments and high performance liquid chromatography assays. Results: Ibrolipim 5 and 50 μmol/L significantly increased cholesterol efflux from THP-1 macrophage-derived foam cells to apoA-I or HDL. Moreover, it upregulated the expression of ABCA1 and ABCG1. In addition, LXRα was also upregulated by the ibrolipim treatment. In addition, LXRα small interfering RNA completely abolished the promotion effect that was induced by ibrolipim. Conclusion: Ibrolipim increased ABCA1 and ABCG1 expression and promoted cholesterol efflux, which was mediated by the LXRα signaling pathway.Keywords: ATP-binding membrane cassette transporter A-1; ATP-binding membrane cassette transporter G-1; ibrolipim; liver X receptor α; atherosclerosis; RNA interference; high density lipoprotein; apolipoprotein; cholesterol Acta Pharmacologica Sinica (2010Sinica ( ) 31: 1343Sinica ( -1349 doi: 10.1038/aps.2010 published online 27 Sep 2010 Original Article # The first two authors contributed equally to this work. * To whom correspondence should be addressed.E-mail tchaoke@yahoo.com.cn Received 2010-04-26 Accepted 2010-08-17 (ABCG1) [4,5] .Ibrolipim is an effective lipoprotein lipase (LPL) activator [6] . It has previously been reported that ibrolipim increases lipoprotein lipase (LPL) mRNA in tissues and LPL activity in postheparin plasma, resulting in a reduction in plasma triglyceride levels and an elevation of HDL. Previous studies from our laboratory and others have also shown that increasing LPL activity in skeletal muscle results in decreased fat accumulation, and long-term administration of ibrolipim protects against the development of experimental atherosclerosis in animals [6][7][8] . However, the detailed mechanism for cholesterol transport proteins induced by ibrolipim is unclear.Recently, our laboratory revealed that the liver X receptors (LXR) synthetic agonist T0901317 promoted ABCA1 gene and protein levels in the aorta, liver, and small intestine of apoE-/-mice and significantly increased cholesterol efflux from peritoneal macrophages [9] . We also showed that IFN-γ may first downregulate the expression of LXRα through the 1344 www.nature.com/aps Chen SG et al Acta Pharmacologica Sinica npg JAK/STAT1 signaling pathway and then decrease expression of ABCA1 and cholesterol efflux in THP-1 macrophagederived foam cells [10] . In addition, eicosapentaenoic acid (EPA) reduces ABCA1 serine phosphorylation and impairs ABCA1-dependent cholesterol efflux through a cAMP/PKA pathway in THP-1 macrophage-derived foam cells [1...

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Section: Discussionmentioning

confidence: 99%

Ibrolipim increases ABCA1/G1 expression by the LXRα signaling pathway in THP-1 macrophage-derived foam cells

et al. 2010

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“…The combination of genome scan studies with more functional approach like differential expression between normal and pathological tissues may help to pick up relevant candidate genes without a priori hypotheses about any biological functions or involvement in the AD process. This strategy, successful to identify several genes in rare autosomal recessive disorders, 30,31 have already been developed to hunt new genetic determinants in multifactorial diseases such as AD. For instance, it has been suggested that genetic variants within the Glutathione-S-transferase omega-1 gene, differentially expressed in the brain of AD cases compared with controls and located on chromosome 10q, may modify age-at-onset of AD.…”

Section: Discussionmentioning

confidence: 99%

Evidence for induction of the ornithine transcarbamylase expression in Alzheimer's disease

et al. 2007

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To more rapidly identify candidate genes located within chromosomal regions of interest defined by genome scan studies in Alzheimer's disease (AD), we have developed a customized microarray containing all the ORFs (n = 2741) located within nine of these regions. Levels of gene expression were assessed in total RNA from brain tissue of 12 controls and 12 AD patients. Of all genes showing differential expression, we focused on the ornithine transcarbamylase (OTC) gene on Xp21.1., a key enzyme of the urea cycle which we found to be expressed in AD brains but not in controls, as confirmed by RT-PCR. We also detected mRNA expression of all the other urea cycle enzymes in AD brains. Immunochemistry experiments revealed that the OTC expression was strictly restricted to vascular endothelial cells in brain. Furthermore, OTC activity was 880% increased in the CSF of probable AD cases compared with controls. We analysed the association of the OTC À389 G/A and À241 A/G promoter polymorphisms with the risk of developing AD. We observed that rare haplotypes may be associated with the risk of AD through a possible modulation of the methylation of the OTC promoter. In conclusion, our results suggest the involvement of a new pathway in AD brains involving the urea cycle.

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“…17,47 Also, the membrane ABC1 transporter plays a key role in the formation of HDL. 48 It is possible that niacin affects the expression of 1 or more of these proteins, and the antioxidant supplements may have interfered with the effect of niacin on the expression of these proteins. Peroxisome proliferator-activated receptor-␣ agonists have been shown to regulate the gene expression of enzymes involved in lipid metabolism and modulate the levels of serum cholesterol, in particular, HDL-C. 49 Similarly, the retinoid X receptor has linked retinoic acid, a ␤-carotene metabolite, with regulation of the promoter region of the apo A-I and ABC1 genes.…”

Section: Discussionmentioning

confidence: 99%

Antioxidant Supplements Block the Response of HDL to Simvastatin-Niacin Therapy in Patients With Coronary Artery Disease and Low HDL

Cheung

Zhao

Chait

et al. 2001

ATVB

177

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Abstract-One strategy for treating coronary artery disease (CAD) patients with low HDL cholesterol (HDL-C) is to maximally increase the HDL-C to LDL-C ratio by combining lifestyle changes with niacin (N) plus a statin. Because HDL can prevent LDL oxidation, the low-HDL state also may benefit clinically from supplemental antioxidants. Lipoprotein changes over 12 months were studied in 153 CAD subjects with low HDL-C randomized to take simvastatin and niacin (S-N), antioxidants (vitamins E and C, ␤-carotene, and selenium), S-N plus antioxidants (S-NϩA), or placebo. Mean baseline plasma cholesterol, triglyceride, LDL-C, and HDL-C levels of the 153 subjects were 196, 207, 127, and 32 mg/dL, respectively. Without S-N, lipid changes were minor. The S-N and S-NϩA groups had comparably significant reductions (PՅ0.001) in plasma cholesterol, triglyceride, and LDL-C. However, increases in HDL-C, especially HDL 2 -C, were consistently higher in the S-N group than in the S-NϩA group (25% vs 18% and 42% vs 0%, respectively). With S-N, but not with S-NϩA, there was a selective increase in apolipoprotein (apo) A-I (64%) in HDL particles containing apo A-I but not A-II [Lp(A-I)] and their particle size. Thus, in CAD patients with low HDL-C, S-N substantially increased HDL 2 -C, Lp(A-I), and HDL particle size. These favorable responses were blunted by the antioxidants used owing to a striking selective effect on Lp(A-I

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The Tangier disease gene product ABC1 controls the cellular apolipoprotein-mediated lipid removal pathway

Cited by 695 publications

References 37 publications

Ibrolipim increases ABCA1/G1 expression by the LXRα signaling pathway in THP-1 macrophage-derived foam cells

Ibrolipim increases ABCA1/G1 expression by the LXRα signaling pathway in THP-1 macrophage-derived foam cells

Evidence for induction of the ornithine transcarbamylase expression in Alzheimer's disease

Antioxidant Supplements Block the Response of HDL to Simvastatin-Niacin Therapy in Patients With Coronary Artery Disease and Low HDL

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