scholarly journals PCSK9: BIOLOGICAL ACTIVITY REGULATION AND CONNECTION WITH LIPID AND CARBOHYDRATE METABOLISM

2017 ◽  
Vol 8 (3) ◽  
pp. 70-75
Author(s):  
A O Averkova
Keyword(s):  
Cholesterol Metabolism ◽  
Ldl Receptor ◽  
Current Data ◽  
Cholesterol Homeostasis ◽  
Lipid Lowering ◽  
Lipid Lowering Therapy ◽  
Dietary Regulation ◽  
Lipoprotein Concentration ◽  
Lipoprotein Uptake ◽  
Consequent Increase

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a serine protease which plays an important role in the regulation of LDL receptor (LDLR) expression and apolipoprotein B (apoB) lipoprotein cholesterol metabolism. It is well known that hepatic PCSK9 expression, its activity and secretion influence cholesterol homeostasis. An upregulation of PCSK9 causes an increase of LDLR degradation, which results in decrease of apoB lipoprotein uptake, and a consequent increase in plasma lipoprotein concentration, including LDL. Therefore, PCSK9 has become a new target for lipid lowering therapy. The aim of this review is to consider current data on metabolic and dietary regulation of PCSK9 and its effect on cholesterol and apoB lipoproteins metabolism and risk of cardiovascular disease.

scholarly journals Atorvastatin Increases the Expression of Long Non-Coding RNAs ARSR and CHROME in Hypercholesterolemic Patients: A Pilot Study

2020 ◽  
Vol 13 (11) ◽  
pp. 382
Author(s):  
Isis Paez ◽  
Yalena Prado ◽  
Carmen G. Ubilla ◽  
Tomás Zambrano ◽  
Luis A. Salazar
Keyword(s):  
Lipid Profile ◽  
Cholesterol Metabolism ◽  
Cholesterol Homeostasis ◽  
Lipid Lowering ◽  
Lipid Lowering Therapy ◽  
Single Nucleotide ◽  
Additional Information ◽  
Before And After ◽  
Non Coding Rnas ◽  
Statin Response

Atorvastatin is extensively used to treat hypercholesterolemia. However, the wide interindividual variability observed in response to this drug still needs further elucidation. Nowadays, the biology of long non-coding RNAs (lncRNAs) is better understood, and some of these molecules have been related to cholesterol metabolism. Therefore, they could provide additional information on variability in response to statins. The objective of this research was to evaluate the effect of atorvastatin on three lncRNAs (lncRNA ARSR: Activated in renal cell carcinoma (RCC) with sunitinib resistance, ENST00000424980; lncRNA LASER: lipid associated single nucleotide polymorphism locus, ENSG00000237937; and lncRNA CHROME: cholesterol homeostasis regulator of miRNA expression, ENSG00000223960) associated with genes involved in cholesterol metabolism as predictors of lipid-lowering therapy performance. Twenty hypercholesterolemic patients were treated for four weeks with atorvastatin (20 mg/day). The lipid profile was determined before and after drug administration using conventional assays. The expression of lncRNAs was assessed in peripheral blood samples by RT-qPCR. As expected, atorvastatin improved the lipid profile, decreasing total cholesterol, LDL-C, and the TC/HDL-C ratio (p < 0.0001) while increasing the expression of lncRNAs ARSR and CHROME (p < 0.0001) upon completion of treatment. LASER did not show significant differences among the groups (p = 0.50). Our results indicate that atorvastatin modulates the expression of cholesterol-related lncRNAs differentially, suggesting that these molecules play a role in the variability of response to this drug; however, additional studies are needed to disclose the implication of this differential regulation on statin response.

Structure and Function of Proprotein Convertase Subtilisin/kexin Type 9 (PCSK9) in Hyperlipidemia and Atherosclerosis

2019 ◽  
Vol 20 (10) ◽  
pp. 1029-1040 ◽  
Author(s):  
Xinjie Lu
Keyword(s):  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Structure And Function ◽  
Lipid Lowering ◽  
Lipid Lowering Therapy ◽  
Proprotein Convertase ◽  
Novel Target ◽  
New Treatments ◽  
And Function

Background:One of the important factors in Low-Density Lipoprotein (LDL) metabolism is the LDL receptor (LDLR) by its capacity to bind and subsequently clear cholesterol derived from LDL (LDL-C) in the circulation. Proprotein Convertase Subtilisin-like Kexin type 9 (PCSK9) is a newly discovered serine protease that destroys LDLR in the liver and thereby controls the levels of LDL in plasma. Inhibition of PCSK9-mediated degradation of LDLR has, therefore, become a novel target for lipid-lowering therapy.Methods:We review the current understanding of the structure and function of PCSK9 as well as its implications for the treatment of hyperlipidemia and atherosclerosis.Results:New treatments such as monoclonal antibodies against PCSK9 may be useful agents to lower plasma levels of LDL and hence prevent atherosclerosis.Conclusion:PCSK9's mechanism of action is not yet fully clarified. However, treatments that target PCSK9 have shown striking early efficacy and promise to improve the lives of countless patients with hyperlipidemia and atherosclerosis.

scholarly journals The Impact of Anthocyanins and Iridoids on Transcription Factors Crucial for Lipid and Cholesterol Homeostasis

2021 ◽  
Vol 22 (11) ◽  
pp. 6074
Author(s):  
Maciej Danielewski ◽  
Agnieszka Matuszewska ◽  
Adam Szeląg ◽  
Tomasz Sozański
Keyword(s):  
Transcription Factors ◽  
Cholesterol Metabolism ◽  
Binding Protein ◽  
Regulatory Element ◽  
Cholesterol Homeostasis ◽  
Lipid Lowering ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Cell Functions ◽  
The Impact

Nutrition determines our health, both directly and indirectly. Consumed foods affect the functioning of individual organs as well as entire systems, e.g., the cardiovascular system. There are many different diets, but universal guidelines for proper nutrition are provided in the WHO healthy eating pyramid. According to the latest version, plant products should form the basis of our diet. Many groups of plant compounds with a beneficial effect on human health have been described. Such groups include anthocyanins and iridoids, for which it has been proven that their consumption may lead to, inter alia, antioxidant, cholesterol and lipid-lowering, anti-obesity and anti-diabetic effects. Transcription factors directly affect a number of parameters of cell functions and cellular metabolism. In the context of lipid and cholesterol metabolism, five particularly important transcription factors can be distinguished: liver X receptor (LXR), peroxisome proliferator-activated receptor-α (PPAR-α), peroxisome proliferator-activated receptor-γ (PPAR-γ), CCAAT/enhancer binding protein α (C/EBPα) and sterol regulatory element-binding protein 1c (SREBP-1c). Both anthocyanins and iridoids may alter the expression of these transcription factors. The aim of this review is to collect and systematize knowledge about the impact of anthocyanins and iridoids on transcription factors crucial for lipid and cholesterol homeostasis.

Intensive Lipid-Lowering Therapy in Patients with Coronary Heart Disease

2005 ◽  
Vol 39 (2) ◽  
pp. 329-334 ◽  
Author(s):  
Stacy A Lauderdale ◽  
Amy Heck Sheehan
Keyword(s):  
Coronary Heart Disease ◽  
Heart Disease ◽  
Density Lipoprotein ◽  
Current Data ◽  
Lipid Lowering ◽  
Lipid Lowering Therapy ◽  
Coronary Syndrome ◽  
Lowering Therapy ◽  
Cardiovascular Morbidity And Mortality ◽  
Stable Coronary Heart Disease

OBJECTIVE: To describe current data evaluating the use of intensive lipid-lowering therapy in patients with coronary heart disease. DATA SOURCES: A literature search using MEDLINE (1966–September 2004) was conducted using the search terms lipoproteins, low-density lipoprotein cholesterol (LDL-C), hydroxymethylglutaryl-coenzyme A reductase inhibitors, coronary arteriosclerosis, and coronary disease to identify published trials comparing the effects of intensive and conventional lipid-lowering therapy. DATA SYNTHESIS: Intensive lipid-lowering therapy reduces LDL-C levels significantly more than conventional treatment and appears to reduce cardiovascular morbidity and mortality in patients who have recently experienced acute coronary syndrome (ACS). However, evidence suggesting clinical benefits in patients with stable coronary heart disease is currently lacking. CONCLUSIONS: Although data are limited, patients with ACS may benefit from intensive lipid-lowering therapy. Several studies are underway to determine the appropriate role of intensive lipid-lowering therapy.

scholarly journals Intensification of lipid-lowering therapy in patients with severe lipid metabolism disorders in specialized lipid control centers. Possibilities of using evolocumab

2020 ◽  
Vol 4 (7) ◽  
pp. 437-444
Author(s):  
O.L. Barbarash ◽  
◽  
V.V. Kashtalap ◽  
N.V. Fedorova ◽  
D.Yu. Sedykh ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Current Data ◽  
Lipid Lowering ◽  
Lipid Lowering Therapy ◽  
Pcsk9 Inhibitors ◽  
Control Center ◽  
Lowering Therapy ◽  
Lipid Metabolism Disorders ◽  
Target Values ◽  
Lipid Control

The article presents current data on the prevalence of dyslipidemia worldwide and in the Russian Federation as the main cardiovascular risk factor of developing diseases associated with atherosclerosis. The article identifies the problems of low-level detection of dyslipidemia in the population and insufficient efficacy of lipid-lowering therapy to achieve the lipid profile target values depending on the established risk. It also presents the possibilities of modern lipid-lowering therapy with the use of innovative drugs — PCSK9 inhibitors and the use of evolocumab in accordance with evidence-based medicine. Adding that, the article shows the experience of two lipid control centers (in Kemerovo and Surgut) with the postulation of the need to expand the lipid control center chain to improve methods for providing medical care to patients with severe forms of dyslipidemia. The possibilities of intensifying lipid-lowering therapy in real clinical practice are outlined on the example of patients undergoing treatment in the lipid control center of Kemerovo. Evolocumab has been shown to be highly effective: reduction of atherogenic cholesterol fractions by 67% from the baseline and high safety of such therapy.KEYWORDS: lipid metabolism disorders, statins, lipid-lowering therapy, familial hypercholesterolemia, PCSK9 inhibitors, evolocumab.FOR CITATION: Barbarash O.L., Kashtalap V.V., Fedorova N.V. et al. Intensification of lipid-lowering therapy in patients with severe lipid metabolism disorders in specialized lipid control centers. Possibilities of using evolocumab. Russian Medical Inquiry. 2020;4(7):437–444. DOI: 10.32364/2587-6821-2020-4-7-437-444.

Abstract 036: LDL-Cholesterol Lowering Among Young Adults Who Experience a First Myocardial Infarction

2017 ◽  
Vol 10 (suppl_3) ◽  
Author(s):  
Bradley Collins ◽  
Avinainder Singh ◽  
Sanjay Divakaran ◽  
Arman Qamar ◽  
Julio Baez ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Ldl Cholesterol ◽  
Current Data ◽  
Young Age ◽  
Lipid Lowering ◽  
Lipid Lowering Therapy ◽  
Billing Data ◽  
Lipid Panel ◽  
The Mean ◽  
One Year

Background: Current data suggest patients who have a myocardial infarction (MI) benefit from aggressive LDL cholesterol (LDL-C) lowering. Consequently, initiation of lipid lowering therapy is a class I recommendation post-MI to reduce the risk of future adverse events. We sought to evaluate LDL-C lowering among patients who experience a first MI at a young age. Methods: Clinical & billing data were used to identify women < 50 years and men < 45 years who had a first MI from two large medical centers. Type of MI was adjudicated by review of medical records, and only patients with a Type 1 MI were included. The magnitude of LDL-C reduction was calculated by comparing the LDL-C pre-MI to the LDL-C one year later. Results: 280 patients (age 42 years ± 5; 35% women) with a complete lipid panel prior to MI and 1 year post-MI were included in this analysis. The mean LDL-C was 123 mg/dL pre-MI, and 82 mg/dL post-MI (p<0.0001). In the entire population, the mean reduction in LDL-C post MI was 27% (95% CI, -32% to -23%), although men had a greater reduction than women (32% vs. 16%, p<0.001). When examining the post-MI LDL-C levels, 214 (76%) reached an LDL-C of <100 mg/dL and 115 (41%) reached an LDL-C of <70 mg/dL. Out of patients who had LDL-C>130mg/dL pre-MI (n=114), 82 (71%) reached an LDL-C of <100 mg/dL, and 35 (30%) reached an LDL-C of <70 mg/dL. Notably, 54 (19%) patients had an LDL-C increase at one year. Conclusions: Among patients experiencing MI at a young age, LDL-C reduction was only modest (27% reduction). Women had a significantly smaller reduction in LDL-C compared with men. Further research is needed to determine the underlying reasons for the sub-optimal reduction in LDL-C, as well as sex specific differences that may account for these disparities.

scholarly journals The Role of Gut Microbiota on Cholesterol Metabolism in Atherosclerosis

2021 ◽  
Vol 22 (15) ◽  
pp. 8074
Author(s):  
Margaret Vourakis ◽  
Gaétan Mayer ◽  
Guy Rousseau
Keyword(s):  
Cardiovascular Health ◽  
Cholesterol Metabolism ◽  
Current Knowledge ◽  
Short Chain Fatty Acids ◽  
Developed Countries ◽  
Current Data ◽  
Cholesterol Homeostasis ◽  
Intestinal Microbes ◽  
Inflammatory Processes

Hypercholesterolemia plays a causal role in the development of atherosclerosis and is one of the main risk factors for cardiovascular disease (CVD), the leading cause of death worldwide especially in developed countries. Current data show that the role of microbiota extends beyond digestion by being implicated in several metabolic and inflammatory processes linked to several diseases including CVD. Studies have reported associations between bacterial metabolites and hypercholesterolemia. However, such associations remain poorly investigated and characterized. In this review, the mechanisms of microbial derived metabolites such as primary and secondary bile acids (BAs), trimethylamine N-oxide (TMAO), and short-chain fatty acids (SCFAs) will be explored in the context of cholesterol metabolism. These metabolites play critical roles in maintaining cardiovascular health and if dysregulated can potentially contribute to CVD. They can be modulated via nutritional and pharmacological interventions such as statins, prebiotics, and probiotics. However, the mechanisms behind these interactions also remain unclear, and mechanistic insights into their impact will be provided. Therefore, the objectives of this paper are to present current knowledge on potential mechanisms whereby microbial metabolites regulate cholesterol homeostasis and to discuss the feasibility of modulating intestinal microbes and metabolites as a novel therapeutic for hypercholesterolemia.

scholarly journals Current Treatment of Familial Hypercholesterolaemia

2014 ◽  
Vol 9 (2) ◽  
pp. 76 ◽  
Author(s):  
Cameron T Lambert ◽  
Pratik Sandesara ◽  
Ijeoma Isiadinso ◽  
Maria Carolina Gongora ◽  
Danny Eapen ◽  
...  
Keyword(s):  
Familial Hypercholesterolaemia ◽  
Lifestyle Modification ◽  
Receptor Gene ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Lipid Lowering ◽  
Atherosclerotic Cardiovascular Disease ◽  
Lipid Lowering Therapy ◽  
Pcsk9 Inhibitors ◽  
Autosomal Dominant Disorder

Familial hypercholesterolaemia is an autosomal-dominant disorder associated with mutations in the LDL receptor gene resulting in markedly elevated plasma low-density lipoprotein cholesterol levels. FH is significantly underrecognised with as many as 1 in 300 having the heterozygous form and 1 in 1 million having the homozygous form of the disease. Early diagnosis and treatment of FH is paramount to reduce the risk of premature atherosclerotic cardiovascular disease and death. The goal of treatment is to reduce LDL-C by 50 % from baseline levels with lifestyle modification, pharmacologic lipid-lowering therapy, LDL apheresis and in rare cases, liver transplantation. Pharmacologic treatment ranges from statin medications to newer agents such as lomitapide, mipomersin and PCSK9 inhibitors. Combination therapy is frequently required to achieve goal lipoprotein level reductions and prevent complications.

Receptor interactions controlling lipoprotein metabolism

1985 ◽  
Vol 63 (8) ◽  
pp. 898-905 ◽  
Author(s):  
Karl H. Weisgraber ◽  
Thomas L. Innerarity ◽  
Stanley C. Rall Jr. ◽  
Robert W. Mahley
Keyword(s):  
Receptor Binding ◽  
Cholesterol Metabolism ◽  
Ldl Receptor ◽  
Lipoprotein Metabolism ◽  
Binding Domain ◽  
Cholesterol Homeostasis ◽  
Lipoprotein Receptor ◽  
Receptor Binding Domain ◽  
Apo B ◽  
Apo E

Lipoprotein receptors play a central role in lipoprotein metabolism and a major role in cholesterol homeostasis. The most completely characterized lipoprotein receptor is the LDL (low density lipoprotein) or apo-B,E(LDL) receptor. The apo-B,E(LDL) receptor is present on both hepatic and extrahepatic cells and is responsible for the metabolism of a major portion of plasma LDL. Binding and internalization of LDL particles by this receptor initiates a series of intracellular events, resulting in the regulation of cellular cholesterol metabolism. In addition to the apo-B on LDL interacting with the apo-B,E(LDL) receptor, the apo-E on apo-E-containing lipoproteins is also capable of interacting and regulating intracellular cholesterol metabolism. The liver has also been shown to contain a second distinct lipoprotein receptor that is specific for apo-E. This receptor has been demonstrated on hepatic membranes from humans, dogs, and swine and is referred to as the apo-E receptor. This receptor may be responsible for the clearance of chylomicron remnants from plasma by the liver and may participate in reverse cholesterol transport. Thus, apo-E is a major determinant in lipoprotein metabolism and cholesterol homeostasis. The receptor binding properties of apo-E are well characterized, and a series of structural variants, several with lipoprotein binding defects, have been identified. Studies of the binding activity of these receptor-defective apo-E variants have helped to define the receptor binding domain of apo-E. These results, in conjunction with receptor binding studies with various apo-E fragments and with an apo-E monoclonal antibody that inhibits receptor binding, have demonstrated that the receptor binding domain is located in the center of the molecule between residues 140 and 160.

scholarly journals Treatment with PCSK9 Inhibitors in Patients with Familial Hypercholesterolemia Lowers Plasma Levels of Platelet-Activating Factor and Its Precursors: A Combined Metabolomic and Lipidomic Approach

Biomedicines ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 1073
Author(s):  
Alessandro Di Minno ◽  
Roberta Clara Orsini ◽  
Mattia Chiesa ◽  
Viviana Cavalca ◽  
Ilenia Calcaterra ◽  
...  
Keyword(s):  
Familial Hypercholesterolemia ◽  
Platelet Activating Factor ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Pleiotropic Effect ◽  
Untargeted Metabolomics ◽  
Lipid Lowering ◽  
P Value ◽  
Lipid Lowering Therapy ◽  
Pcsk9 Inhibitors

Introduction: Familial hypercholesterolemia (FH) is characterized by extremely high levels of circulating low-density lipoprotein cholesterol (LDL-C) and is caused by mutations of genes involved in LDL-C metabolism, including LDL receptor (LDLR), apolipoprotein B (APOB), or proprotein convertase subtilisin/Kexin type 9 (PCSK9). Accordingly, PCSK9 inhibitors (PCSK9i) are effective in LDL-C reduction. However, no data are available on the pleiotropic effect of PCSK9i. To this end, we performed an untargeted metabolomics approach to gather a global view on changes in metabolic pathways in patients receiving treatment with PCSK9i. Methods: Twenty-five FH patients starting treatment with PCSK-9i were evaluated by an untargeted metabolomics approach at baseline (before PCSK9i treatment) and after 12 weeks of treatment. Results: All the 25 FH subjects enrolled were on maximal tolerated lipid-lowering therapy prior to study entry. After a 12 week treatment with PCSK9i, we observed an expected significant reduction in LDL-cholesterol levels (from 201.0 ± 69.5 mg/dL to 103.0 ± 58.0 mg/dL, p < 0.001). The LDL-C target was achieved in 36% of patients. After peak validation and correction, after 12 weeks of PCSK9i treatment as compared to baseline, we observed increments in creatine (p-value = 0.041), indole (p-value = 0.045), and indoleacrylic acid (p-value= 0.045) concentrations. Conversely, significant decreases in choline (p-value = 0.045) and phosphatidylcholine (p-value < 0.01) together with a reduction in platelet activating factor (p-value = 0.041) were observed. Conclusions: Taking advantage of untargeted metabolomics, we first provided evidence of concomitant reductions in inflammation and platelet activation metabolites in FH patients receiving a 12 week treatment with PCSK9i.

Sign in / Sign up

Export Citation Format

Share Document