Search results for "PCSK9"

Reduced VLDL clearance in ApoeNpc1 mice is associated with increased Pcsk9 and Idol expression and decreased hepatic LDL-receptor levels

2010

Niemann-Pick type C1 (NPC1) promotes the transport of LDL receptor (LDL-R)-derived cholesterol from late endosomes/lysosomes to other cellular compartments. NPC1-deficient cells showed impaired regulation of liver_X receptor (LXR) and sterol regulatory element-binding protein (SREBP) target genes. We observed that Apoe(-/-)Npc1(-/-) mice displayed a marked increase in total plasma cholesterol mainly due to increased VLDL, reflecting decreased clearance. Although nuclear SREBP-2 and Ldlr mRNA levels were increased in Apoe(-/-)Npc1(-/-) liver, LDL-R protein levels were decreased in association with marked induction of proprotein convertase subtilisin/kexin type 9 (Pcsk9) and inducible degrade…

Familial hypercholesterolæmia in children and adolescents: Gaining decades of life by optimizing detection and treatment

2015

Contains fulltext : 155263.pdf (Publisher’s version ) (Open Access) Familial hypercholesterolaemia (FH) is a common genetic cause of premature coronary heart disease (CHD). Globally, one baby is born with FH every minute. If diagnosed and treated early in childhood, individuals with FH can have normal life expectancy. This consensus paper aims to improve awareness of the need for early detection and management of FH children. Familial hypercholesterolaemia is diagnosed either on phenotypic criteria, i.e. an elevated low-density lipoprotein cholesterol (LDL-C) level plus a family history of elevated LDL-C, premature coronary artery disease and/or genetic diagnosis, or positive genetic testin…

Inclisiran: a small interfering RNA strategy targeting PCSK9 to treat hypercholesterolemia

2022

Introduction: Inclisiran is a novel posttranscriptional gene silencing therapy that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9) synthesis by RNA interference and has a potent, dose-dependent, durable effect in lowering LDL-C, and therefore is an effective drug to treat dyslipidemia, reducing the risk for acute cardiovascular (CV) events. It is safe and well-tolerated. Areas covered: This paper aims to review the mechanism of action of inclisiran while evaluating its efficacy and safety in the treatment of dyslipidemia from data of the clinical trials in the ORION program. Expert opinion: Data from the clinical trials in the ORION program demonstrated efficacy and safety o…

Lomitapide does not alter PCSK9 and Lp(a) levels in homozygous familial hypercholesterolemia patients: analysis on cytokines and lipid profile

2021

Abstract Lomitapide, a drug for the treatment of homozygous familial hypercholesterolemia patients, reduced total and LDL cholesterol but no significant changes were observed on PCSK9 and Lp(a) plasma levels. Some changes of inflammatory mediators were also observed, including hsCRP, which may suggest an anti-inflammatory effect.

Insight into the Evolving Role of PCSK9

2022

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is the last discovered member of the family of proprotein convertases (PCs), mainly synthetized in hepatic cells. This serine protease plays a pivotal role in the reduction of the number of low-density lipoprotein receptors (LDLRs) on the surface of hepatocytes, which leads to an increase in the level of cholesterol in the blood. This mechanism and the fact that gain of function (GOF) mutations in PCSK9 are responsible for causing familial hypercholesterolemia whereas loss-of-function (LOF) mutations are associated with hypocholesterolemia, prompted the invention of drugs that block PCSK9 action. The high efficiency of PCSK9 inhibitors (…

Exenatide prevents statin-related LDL receptor increase and improves insulin secretion in pancreatic beta cells (1.1E7) in a protein kinase A-depende…

2022

Statins are primary drugs in the treatment of hyperlipidemias. This group of drugs is known for its beneficial pleiotropic effects (e.g., reduction of inflammatory state). However, a growing body of evidence suggests its diabetogenic properties. The culpable mechanism is not completely understood and might be related to the damage to pancreatic beta cells. Therefore, we conceived an in vitro study to explore the impact of atorvastatin on pancreatic islet beta cells line (1.1.E7). We evaluated the influence on viability, insulin, lowdensity lipoprotein (LDL) receptor, and proprotein convertase subtilisin/kexin type 9 (PCSK9) expression. A significant drop in mRNA for proinsulin and insulin e…

Hypobetalipoproteinemia

2011

Hypobetalipoproteinemias (HBL) represent a heterogeneous group of disorders characterized by reduced plasma levels of total cholesterol (TC), low density lipoprotein-cholesterol (LDL-C) and apolipoprotein B (apoB) below the 5th percentile of the distribution in the population. HBL are defined as primary or secondary according to the underlying causes. Primary monogenic HBL are caused by mutations in several known genes (APOB, PCSK9, MTP, SARA2) or mutations in genes not yet identified. Familial hypobetalipoproteinemia (FHBL) is the most frequent monogenic form of HBL with a dominant mode of inheritance. It may be due to loss-of-function mutations in APOB or, less frequently, in PCSK9 genes.…

A NOVEL LOSS OF FUNCTION MUTATION OF PCSK9 GENE

2006

Periphere arterielle Verschlusskrankheit: Wann ist ein PCSK9-Inhibitor sinnvoll?

2018

ZusammenfassungDie Leitlinie der Europäischen Gesellschaft für Kardiologie empfiehlt bei Patienten mit manifester peripherer arterieller Verschlusskrankheit (PAVK) ebenso wie bei KHK oder zerebrovaskulärer Erkrankung einen LDL-C-Zielwert < 70 mg/dL oder eine Reduktion um 50 %, wenn der Ausgangswert zwischen 70 und 135 mg/dL liegt. Die Applikation eines PCSK9-Inhibitors ermöglicht die Zielwerterreichung für viele Patienten, die dies unter einer maximalen Statintherapie in Kombination mit Ezetemib nicht erreichen. In der Fourier-Studie konnte für Patienten mit PAVK, die bei Studieneinschluss weder einen Myokardinfarkt noch einen Apoplex erlitten hatten, eine deutliche Risikoreduktion (RR) …

Targeting PCSK9 for therapeutic gains: Have we addressed all the concerns?

2016

Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) regulates the expression of low-density lipoprotein (LDL)-receptors, through reducing their recycling by binding to the receptor along with LDL and targeting it for lysosomal destruction. PCSK9 also enhances the degradation of very-low-density-lipoprotein receptor (VLDLR) and lipoprotein receptor-related protein 1 (LRP-1) in a LDL-receptor independent manner. This role in lipid homeostasis presents PCSK9 as an attractive target for the therapeutic management of familial hypercholesterolemia as well as other refractory dyslipidaemias. However, PCSK9 mediates multifarious functions independent of its role in lipid homeostasis, which can be…