scholarly journals The PCSK9 revolution and the potential of PCSK9-based therapies to reduce LDL-cholesterol

2017 ◽  
Vol 2017 (1) ◽  
Author(s):  
Nabil G Seidah
Keyword(s):  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Cholesterol Absorption ◽  
Cardiovascular Death ◽  
Cardiovascular Complications ◽  
Inherited Disease ◽  
Reductase Inhibitors ◽  
Target Values ◽  
Niemann Pick ◽  
Coa Reductase

[first paragraph of article]A large number of clinical trials over the last 30 years have firmly consolidated the importance of lowering low density lipoprotein cholesterol (LDLc) in the prevention of cardiovascular diseases (CVD) and its associated devastating sequelae. While healthy diets and exercise are highly recommended to lower LDLc levels, in many individuals with high baseline levels of LDLc, this is not sufficient to bring levels down to recommended target values in order to prevent recurrent coronary heart disease and cardiovascular complications. This is especially true for patients at high risk of premature cardiovascular death and disability, including those with familial hypercholesterolaemia (FH). FH is a very common inherited disease – affecting at least 30 million people worldwide, with an overall incidence of 1:200 globally – of whom ≤ 1% have been diagnosed. The advent of HMG-CoA reductase inhibitors, also known as ‘‘statins’’, and their first application to hypercholesterolemic patients over 30 years ago, has revolutionized the treatment of FH patients and resulted in substantial lowering of LDLc. In addition, cholesterol– lowering drugs, such as ‘‘ezetimibe’’ that blocks cholesterol absorption from the gut by inhibiting the Niemann-Pick C1-like 1 (NPC1L1) transporter, have also been successful and a 7-year IMPROVE-IT trial revealed that a ‘‘simvastatin-ezetimibe’’ combination resulted in an incremental lowering of LDLc levels and a modest 2% improved cardiovascular outcomes.3 Therefore, it became clear that additional treatments are needed to substantially decrease LDLc and efficiently protect against CVD. 

scholarly journals SAT-456 Reduced Cholesterol Absorption and Synthesis Markers in Patients with Hyperthyroidism Due to Graves’ Disease

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Tomoko Nagamine ◽  
Kyoko Inagaki ◽  
Shunsuke Kobayashi ◽  
Yuki Shuto ◽  
Mototsugu Nagao ◽  
...  
Keyword(s):  
Cholesterol Synthesis ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Cholesterol Absorption ◽  
Surface Expression ◽  
Cell Surface Expression ◽  
Graves Disease ◽  
Euthyroid State ◽  
Niemann Pick ◽  
Coa Reductase

Abstract Background:Thyroid hormones have been reported to promote cell-surface expression of low-density lipoprotein receptor (LDL-R), and also increase mRNA expression of HMG-CoA reductase at the same time. Since LDL cholesterol (LDL-C) uptake via LDL-R is relatively superior to cholesterol synthesis in hyperthyroidism, plasma LDL-C levels can be lower as compared to euthyroid state. Conversely, hypothyroidism can increase plasma LDL-C levels because cholesterol absorption via Niemann-Pick C1-like 1 has been suggested to increase in hypothyroidism. However, there have been no reports about changes of cholesterol absorption and synthesis markers by the treatment of hyperthyroidism in patients with Graves’ disease. Patients and method: We collected plasma samples from patients with hyperthyroidism, who were diagnosed as Graves’ disease (n=17, M/F: 4/13, age: 24-70 years old). Thyroid hormones, general lipid profiles (Total cholesterol: TC, LDL-C, high-density lipoprotein cholesterol: HDL-C and triglyceride: TG), apolipoproteins, markers of cholesterol synthesis (lathosterol) and absorption (campesterol, sitosterol, cholestanol), lipoprotein lipase (LPL), and proprotein convertase subtilisin/kexin type 9 (PCSK9) were analyzed before treatment, and at euthyroid state (eu), 3 and 6 months after attaining euthyroid state (eu-3M and eu-6M). Result: It took 159.2±108.6 days to attain euthyroid state by the thiamazole treatment. TC, LDL-C and HDL-C levels were increased at eu (TC, 144.5±26.7 to 225.0±61.6; LDL-C, 77.8±20.9 to 138.9±43.9; HDL-C, 49.7±12.6 to 67.9±20.0 mg/dL: P<0.0001 vs before treatment, respectively). Such changes remained at eu-3M and eu-6M. TG was not changed at eu, but significantly increased at eu-6M (85.0±49.1 to 113.7±60.8 mg/dL, P=0.02). Cholesterol absorption markers were increased at eu, eu-3M and eu-6M (e.g. campesterol, 2.6±1.2 to 4.9±2.3; sitosterol, 1.5±0.6 to 2.9±1.4; cholestanol, 1.9±0.6 to 3.2±1.1 μg/mL: P<0.0001, eu vs before treatment, respectively). Cholesterol synthesis marker was increased at eu, eu-3M and eu-6M (e.g. lathosterol, 1.8±0.7 to 2.3±0.9 μg/mL: P=0.005, eu vs before treatment). Both LPL and PCSK9 were also increased at eu, eu-3M and eu-6M. Conclusion: These data suggest that both cholesterol absorption and synthesis are downregulated in patients with hyperthyroidism due to Graves’ disease and can be restored by attaining euthyroid state. In turn, LDL-C and TG levels should be carefully monitored during the treatment of Graves’ disease because hyperlipidemia could emerge in euthyroid state.

scholarly journals Sex, Prescribing Practices and Guideline Recommended, Blood Pressure, and LDL Cholesterol Targets at Baseline in the BARI 2D Trial

2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
Michelle F. Magee ◽  
Jacqueline E. Tamis-Holland ◽  
Jiang Lu ◽  
Vera A. Bittner ◽  
Maria Mori Brooks ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Sex Differences ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Prescribing Practices ◽  
Cvd Risk ◽  
Established Coronary Artery Disease ◽  
Reductase Inhibitors ◽  
Artery Disease ◽  
Coa Reductase

Background.Research has shown less aggressive treatment and poorer control of cardiovascular disease (CVD) risk factors in women than men.Methods.We analyzed sex differences in pharmacotherapy strategies and attainment of goals for hemoglobin A1c (HbA1c), blood pressure (BP), and low density lipoprotein cholesterol (LDL-C) in patients with type 2 diabetes and established coronary artery disease enrolled into the BARI 2D trial.Results.Similar numbers of drugs were prescribed in both women and men. Women were less frequent on metformin or sulfonylurea and more likely to take insulin and to be on higher doses of hydroxymethylglutaryl-CoA reductase inhibitors (statins) than men. After adjusting for baseline differences and treatment prescribed, women were less likely to achieve goals for HbA1c (OR = 0.71, 95% CI 0.57, 0.88) and LDL-C (OR = 0.64, 95% CI 0.53, 0.78). More antihypertensives were prescribed to women, and yet BP ≤ 130/80 mmHg did not differ by sex.Conclusions.Women entering the BARI 2D trial were as aggressively treated with drugs as men. Despite equivalent treatment, women less frequently met targets for HbA1c and LDL-C. Our findings suggest that there may be sex differences in response to drug therapies used to treat diabetes, hypertension, and hyperlipidemia.

HMG-CoA reductase inhibitors suppress macrophage growth induced by oxidized low density lipoprotein

1997 ◽  
Vol 133 (1) ◽  
pp. 51-59 ◽  
Author(s):  
Masakazu Sakai ◽  
Shozo Kobori ◽  
Takeshi Matsumura ◽  
Takeshi Biwa ◽  
Yoshihiro Sato ◽  
...  
Keyword(s):  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Low Density ◽  
Oxidized Low Density Lipoprotein ◽  
Hmg Coa Reductase ◽  
Reductase Inhibitors ◽  
Hmg Coa Reductase Inhibitors ◽  
Coa Reductase

scholarly journals The Chylomicron: Relationship to Atherosclerosis

2012 ◽  
Vol 2012 ◽  
pp. 1-13 ◽  
Author(s):  
Gerald H. Tomkin ◽  
Daphne Owens
Keyword(s):  
Cholesterol Synthesis ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Cholesterol Absorption ◽  
Structural Protein ◽  
Chylomicron Particle ◽  
Niemann Pick ◽  
Chylomicron Formation ◽  
The Relationship ◽  
Ldl Composition

The B-containing lipoproteins are the transporters of cholesterol, and the evidence suggests that the apo B48-containing postprandial chylomicron particles and the triglyceride-rich very low density lipoprotein (VLDL) particles play an important part in the development of the plaque both directly and indirectly by their impact on LDL composition. The ratio of dietary to synthesised cholesterol is variable but tightly regulated: hence intervention with diet at best reduces serum cholesterol by <20% andusually <10%. Statins are the mainstay of cholesterol reduction therapy, but they increase cholesterol absorption, an example of the relationship between synthesis and absorption. Inhibition of cholesterol absorption with Ezetimibe, an inhibitor of Niemann Pick C1-like 1 (NPC1-L1), the major regulator of cholesterol absorption, increases cholesterol synthesis and hence the value of adding an inhibitor of cholesterol absorption to an inhibitor of cholesterol synthesis. Apo B48, the structural protein of the chylomicron particle, is synthesised in abundance so that the release of these particles is dependent on the amount of cholesterol and triglyceride available in the intestine. This paper will discuss cholesterol absorption and synthesis, chylomicron formation, and the effect of postprandial lipoproteins on factors involved in atherosclerosis.

Association between non-responsiveness to plant sterol intervention and polymorphisms in cholesterol metabolism genes: a case-control study

2008 ◽  
Vol 33 (4) ◽  
pp. 728-734 ◽  
Author(s):  
Iwona Rudkowska ◽  
Suhad S. AbuMweis ◽  
Catherine Nicolle ◽  
Peter J.H. Jones
Keyword(s):  
Plant Sterol ◽  
Cholesterol Metabolism ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Cholesterol Absorption ◽  
Individual Variability ◽  
Nucleotide Polymorphisms ◽  
Control Phase ◽  
Individual Variations ◽  
Niemann Pick

Plant sterol (PS) consumption decreases low-density lipoprotein cholesterol (LDL-C) levels; however, high variability of responsiveness of lipid levels to PS intervention has been observed. We hypothesized that common single-nucleotide polymorphisms (SNPs) in the genes for the ATP binding cassette proteins G5 (ABCG5) and G8 (ABCG8), Niemann-Pick C1-like 1 (NPC1L1), or other proteins of the cholesterol pathway, would underline inter-individual variations in response to PS. Twenty-six hyperlipidemic subjects completed a randomized trial of 3 PS phases and a control phase. Three non-responders were identified who failed on 3 consecutive occasions to decrease either total cholesterol or LDL-C level vs. control. It was observed that after 3 PS phases compared with a control phase, cholesterol absorption changed to a lesser degree (–7.7% ± 10.8%) in the non-responders than in the top 3 responders (–22.1% ± 8.8%); however, cholesterol synthesis rates did not differ between sub-groups. No common polymorphisms in ABCG8, ABCG5, or NPC1L1 were demonstrated between the 3 top responders and the non-responders. Yet, 1 non-responsive subject did demonstrate a rare SNP in NPC1L1. Results indicate PS intake did not decrease cholesterol absorption rates to the same degree in certain subjects, possibly clarifying the inter-individual variability in the cholesterol-lowering effect; hence, this work should be expanded.

P-Glycoprotein Is Downregulated in KG1a Primitive Leukaemia Cells by LDL Cholesterol Deprivation and by HMG-CoA Reductase Inhibitors.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4192-4192
Author(s):  
Laura Connelly-Smith ◽  
Joanne Pattinson ◽  
Martin Grundy ◽  
Shili Shang ◽  
Claire Seedhouse ◽  
...  
Keyword(s):  
Ldl Cholesterol ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Hmg Coa Reductase ◽  
Serum Free ◽  
Reductase Inhibitors ◽  
P Glycoprotein ◽  
Hmg Coa Reductase Inhibitors ◽  
Coa Reductase ◽  
And Function

Abstract P-glycoprotein (pgp) is a membrane transporter encoded by the multidrug resistance (MDR1, ABCB1) gene. Pgp is a poor prognostic factor in elderly patients with acute myeloid leukaemia (AML). In addition to its role in drug efflux, pgp has been implicated in cellular cholesterol homeostasis. We investigated the effects of exogenous cholesterol removal on pgp expression and function. KG1a drug-naïve, primitive leukaemia cells were cultured in serum free medium with or without the addition of low density lipoprotein (LDL) cholesterol. After 72 hours pgp expression and function was assessed by flow cytometry and total cholesterol content of the KG1a cells was determined by the Amplex Red® cholesterol assay. The addition of clinically available cholesterol lowering agents, HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase inhibitors to KG1a cells was also assessed. There was a 39% (SEM 8.3% P=0.03) decrease in pgp protein expression after 3 days of serum free culture without HMG-CoA reductase inhibitors. Message was decreased by 40% (P=0.01) and pgp function was also reduced by 40% (P=0.005). The addition of low density lipoprotein (LDL) cholesterol restored pgp expression to 86% of the basal value. The addition of a HMG-CoA reductase inhibitor to KG1a cells in serum free culture resulted in a further 26% (lovastatin, P=0.03) and 16% (pravastatin, P=0.05) reduction in pgp respectively. Lovastatin also significantly reduced cellular cholesterol levels by 47% (P=0.002) under serum free conditions. Furthermore, the toxicity of the pgp substrate drug daunorubicin was significantly enhanced following lovastatin pre-culture (P=0.04). We conclude that LDL/cholesterol contributes to pgp expression and chemoresistance in primitive leukaemia cells. The use of HMG-CoA reductase inhibitors may be of clinical value in lowering pgp expression in AML.

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