HMG-CoA Reductase Inhibitor, Simvastatin Improves Reverse Cholesterol Transport in Type 2 Diabetic Patients with Hyperlipidemia

Guan, Jian-Long; Tamasawa, Naoki; Murakami, Hiroshi; Matsui, Jun; Tanabe, Jutaro; Matsuki, Kota; Yamashita, Maki; Suda, Toshio

doi:10.5551/jat.e512

Cited by 31 publications

(27 citation statements)

References 34 publications

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“…On the contrary, pravastatin did not change the mRNA expression and protein ABCA1 in leukocytes of mice [13] and simvastatin increased ABCA1 levels in PBMCs of Type II diabetes patients in vivo [35]. However, differences between human and mice cholesterol metabolism and the absence of diabetic patients in our study may explain the different findings.…”

Section: Pharmacogenomics (2010) 11(9)contrasting

confidence: 56%

Effects of Lipid-Lowering Drugs on Reverse Cholesterol Transport Gene Expressions in Peripheral Blood Mononuclear and Hepg2 Cells

et al. 2010

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Aims:The ATP-binding cassette transporters, ABCA1 and ABCG1, are LXR-target genes that play an important role in reverse cholesterol transport. We examined the effects of inhibitors of the cholesterol absorption (ezetimibe) and synthesis (statins) on expression of these transporters in HepG2 cells and peripheral blood mononuclear cells (PBMCs) of individuals with primary (and nonfamilial) hypercholesterolemia (HC). Materials & methods:A total of 48 HC individuals were treated with atorvastatin (10 mg/day/4 weeks) and 23 were treated with ezetimibe (10 mg/day/4 weeks), followed by simvastatin (10 mg/day/8 weeks) and simvastatin plus ezetimibe (10 mg of each/day/4 weeks). Gene expression was examined in statin-or ezetimibe-treated and control HepG2 cells as well as PBMCs using real-time PCR. Results: In PBMCs, statins and ezetimibe downregulated ABCA1 and ABCG1 mRNA expression but did not modulate NR1H2 (LXR-b) and NR1H3 (LXR-a) levels. Positive correlations of ABCA1 with ABCG1 and of NR1H2 with NR1H3 expressions were found in all phases of the treatments. In HepG2 cells, ABCA1 mRNA levels remained unaltered while ABCG1 expression was increased by statin (1.0-10.0 µM) or ezetimibe (5.0 µM) treatments. Atorvastatin upregulated NR1H2 and NR1H3 only at 10.0 µM, meanwhile ezetimibe (1.0-5.0 µM) downregulated NR1H2 but did not change NR1H3 expression. Conclusion: Our findings reveal that lipid-lowering drugs downregulate ABCA1 and ABCG1 mRNA expression in PBMCs of HC individuals and exhibit differential effects on HepG2 cells. Moreover, they indicate that the ABCA1 and ABCG1 transcript levels were not correlated directly to LXR mRNA expression in both cell models treated with lipid-lowering drugs.KEYWORDS: ABCA1 n ABCG1 n ezetimibe n mRNA expression n PBMC n statins

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Section: Pharmacogenomics (2010) 11(9)contrasting

confidence: 56%

Effects of Lipid-Lowering Drugs on Reverse Cholesterol Transport Gene Expressions in Peripheral Blood Mononuclear and Hepg2 Cells

et al. 2010

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“…Although the details and the pathogenesis of low-HDL cholesterolemia and increased risk of atherosclerosis are not well understood, a higher risk of coronary artery disease (CAD) in type 2 diabetic patients might be attributed to a reduced reverse cholesterol transport (RCT) system 2) . Adenosine triphosphate (ATP)-binding cassette transporter (ABC) A1 has been identified as a pivotal gene in the regulation of both plasma HDL cholesterol levels and cellular cholesterol homeostasis, which is a key molecule in the first step of RCT.…”

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confidence: 99%

Genotypic Effect of ABCG1 Gene Promoter -257T>G Polymorphism on Coronary Artery Disease Severity in Japanese Men

Furuyama

Uehara

Zhang

et al. 2009

JAT

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Aim: ATP-binding cassette transporter G1 (ABCG1) is a cholesterol transporter that plays a role in cholesterol efflux in the presence of high-density lipoprotein (HDL). Moreover, HDL-mediated cholesterol efflux is increased in cultured ABCG1 overexpressed cells; however, the physiological roles of ABCG1 and its contribution to atherosclerosis in humans remain unclear. Methods: The effect of ABCG1 257T G mutation on transcription activity was determined by a reporter assay. One hundred nine Japanese men with coronary artery disease (CAD) were analyzed. ABCG1 257T G polymorphism was assessed by mutation-selective PCR methods to identify T/T, T/G, and G/G genotypes. Results:The reporter assay showed that ABCG1 transcription activity was significantly lower (p 0.01) in the G allele of 257T G polymorphism compared with that in the T allele. Clinically, there were no significant differences in serum triglyceride and total, LDL, and HDL cholesterol levels, or other risk factors. Logistic regression analysis revealed significant additive and dominant effects on the frequency of patients with multi-vessel disease compared with single-vessel disease

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“…In particular, abdominal obesity is associated with increased cardiovascular risk factors, elevated blood pressure, increased triglycerides, fasting glucose, and decreased high-density lipoprotein cho-blockade may be potentially beneficial against atherosclerosis 5) . The reverse cholesterol transport (RCT) is one of the major protective systems against atherosclerosis 6,7) . Recently, ATP-binding cassette (ABC) transporter G1 was found to induce an alternative cholesterol efflux pathway from macrophages and prevent cellular lipid accumulation 8,9) .…”

Section: Introductionmentioning

confidence: 99%

Cannabinoid 1 Receptor Blockade Reduces Atherosclerosis with Enhances Reverse Cholesterol Transport

Sugamura

Sugiyama

Fujiwara

et al. 2010

JAT

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Aim: A recent clinical study using coronary intravascular ultrasound showed that rimonabant, a cannabinoid 1 (CB1) receptor antagonist, significantly reduced total atheroma volume, suggesting that CB1 receptor blockade could be beneficial in anti-atherogenic therapy. The reverse cholesterol transport (RCT) system plays important roles in atherogenesis. We investigated whether CB1 receptor blockade could modulate atherogenesis in mice. Methods and Results: Oral administration of rimonabant (8 mg/kg/day) to apolipoprotein E-deficient mice for 3 months significantly reduced the relative area of atherosclerotic lesions in the aorta (vehicle; 12.6 4.0% vs. rimonabant; 9.7 2.3, n 12 each, p 0.05) with an increase in serum adiponectin levels (15.6 2.3 g/mL vs. 12.2 2.1, n 12 each, p 0.001), without affecting body weight or serum cholesterol levels. Rimonabant tended to increase serum high-density lipoprotein cholesterol (HDL-C) (p 0.05). The relative area of atherosclerotic lesions in the aorta correlated inversely with serum HDL-C levels (r 0.45, n 24, p 0.05). Rimonabant upregulated the mRNA expression levels of various components of the RCT system on THP-1 cell-derived macrophages (scavenger receptor B1: 1.15 0.12 fold, n 6; p 0.05, ATP-binding cassette [ABC] transporter G1: 1.23 0.11 fold, n 6; p 0.01), but not ABCA1 (1.13 0.20 fold, n 6; p 0.13). Conclusion: CB1 receptor blockade reduced atherosclerosis in apoE-deficient mice through an increase in serum adiponectin levels and activation of the RCT system. CB1 receptor blockade may be therapeutically beneficial for atherogenesis by increasing the serum adiponectin level and enhancing of the RCT system.

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HMG-CoA Reductase Inhibitor, Simvastatin Improves Reverse Cholesterol Transport in Type 2 Diabetic Patients with Hyperlipidemia

Cited by 31 publications

References 34 publications

Effects of Lipid-Lowering Drugs on Reverse Cholesterol Transport Gene Expressions in Peripheral Blood Mononuclear and Hepg2 Cells

Effects of Lipid-Lowering Drugs on Reverse Cholesterol Transport Gene Expressions in Peripheral Blood Mononuclear and Hepg2 Cells

Genotypic Effect of ABCG1 Gene Promoter -257T>G Polymorphism on Coronary Artery Disease Severity in Japanese Men

Cannabinoid 1 Receptor Blockade Reduces Atherosclerosis with Enhances Reverse Cholesterol Transport

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