scholarly journals A randomized trial and novel SPR technique identifies altered lipoprotein-LDL receptor binding as a mechanism underlying elevated LDL-cholesterol in APOE4s

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
M. V. Calabuig-Navarro ◽  
K. G. Jackson ◽  
C. F. Kemp ◽  
D. S. Leake ◽  
C. M. Walden ◽  
...  
Keyword(s):  
Randomized Trial ◽  
Receptor Binding ◽  
Ldl Cholesterol ◽  
Ldl Receptor

scholarly journals Plasma PCSK9 Concentrations Correlate with LDL and Total Cholesterol in Diabetic Patients and Are Decreased by Fenofibrate Treatment

2008 ◽  
Vol 54 (6) ◽  
pp. 1038-1045 ◽  
Author(s):  
Gilles Lambert ◽  
Nicolas Ancellin ◽  
Francesca Charlton ◽  
Daniel Comas ◽  
Julia Pilot ◽  
...  
Keyword(s):  
Ldl Cholesterol ◽  
Polyclonal Antibodies ◽  
Sandwich Elisa ◽  
Ldl Receptor ◽  
Hdl Cholesterol ◽  
Diabetic Patients ◽  
Plasma Triglycerides ◽  
Fenofibrate Treatment ◽  
Before And After ◽  
Fenofibrate Intervention

Abstract Background: Proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes the degradation of the LDL receptor (LDLr) in hepatocytes, and its expression in mouse liver has been shown to decrease with fenofibrate treatment. Methods: We developed a sandwich ELISA using recombinant human PCSK9 protein and 2 affinity-purified polyclonal antibodies directed against human PCSK9. We measured circulating PCSK9 concentrations in 115 diabetic patients from the FIELD (Fenofibrate Intervention and Event Lowering in Diabetes) study before and after fenofibrate treatment. Results: We found that plasma PCSK9 concentrations correlate with total (r = 0.45, P = 0.006) and LDL (r = 0.54, P = 0.001) cholesterol but not with triglycerides or HDL cholesterol concentrations in that cohort. After 6 weeks of treatment with comicronized fenofibrate (200 mg/day), plasma PCSK9 concentrations decreased by 8.5% (P = 0.041 vs pretreatment). This decrease correlated with the efficacy of fenofibrate, as judged by a parallel reduction in plasma triglycerides (r = 0.31, P = 0.015) and LDL cholesterol concentrations (r = 0.27, P = 0.048). Conclusions: We conclude that this decrease in PCSK9 explains at least in part the LDL cholesterol–lowering effects of fenofibrate. Fenofibrate might be of interest to further reduce cardiovascular risk in patients already treated with a statin.

Expression of LDL Receptor Binding Determinants in Very Low Density Lipoproteinsa

1985 ◽  
Vol 454 (1) ◽  
pp. 239-247 ◽  
Author(s):  
WILLIAM A. BRADLEY ◽  
ANTONIO M. GOTTO ◽  
SANDRA H. GIANTURCO
Keyword(s):  
Receptor Binding ◽  
Ldl Receptor ◽  
Low Density ◽  
Binding Determinants

scholarly journals Familial Hypercholesterolemia: Three “under” (Understood, Underdiagnosed, and Undertreated) Disease

2021 ◽  
Author(s):  
Vladimir O. Konstantinov
Keyword(s):  
Familial Hypercholesterolemia ◽  
Time Course ◽  
Ldl Cholesterol ◽  
Genetic Disorders ◽  
Receptor Gene ◽  
Ldl Receptor ◽  
Hdl Cholesterol ◽  
Blood Cholesterol ◽  
Healthy Population ◽  
Loss Of Function

Familial hypercholesterolemia (FH) is one of the most prevalent genetic disorders leading to premature atherosclerosis and coronary heart disease. The main cause of FH is a mutation in the LDL-receptor gene that leads to loss of function of these receptors causing high levels of blood cholesterol. The diagnosis of FH is not very easy. Wide screenings are needed to reveal high levels of LDL cholesterol among “healthy” population. If the patient has MI or stroke at an early age, high levels of LDL cholesterol, and tendon xanthomas, the diagnosis of FH becomes much more clear. Genetic testing is a gold standard in the diagnosis of FH. There are several factors, influencing the time course of FH. Smoking males with low levels of HDL cholesterol have an extremely higher risk of death than nonsmoking females with high HDL cholesterol. Management of FH includes low cholesterol diet, statin and ezetimibe treatment, PCSK inhibitors, and LDL aphaeresis. Early and effective treatment influences much the prognosis in FH patients.

scholarly journals FXR activation by obeticholic acid or nonsteroidal agonists induces a human-like lipoprotein cholesterol change in mice with humanized chimeric liver

2018 ◽  
Vol 59 (6) ◽  
pp. 982-993 ◽  
Author(s):  
Romeo Papazyan ◽  
Xueqing Liu ◽  
Jingwen Liu ◽  
Bin Dong ◽  
Emily M. Plummer ◽  
...  
Keyword(s):  
Target Gene ◽  
Ldl Cholesterol ◽  
Ldl Receptor ◽  
Hdl Cholesterol ◽  
Farnesoid X Receptor ◽  
Receptor Protein ◽  
Chimeric Mice ◽  
Obeticholic Acid ◽  
Protein Levels ◽  
Mechanistic Basis

Obeticholic acid (OCA) is a selective farnesoid X receptor (FXR) agonist that regulates bile acid and lipid metabolism. FXR activation induces distinct changes in circulating cholesterol among animal models and humans. The mechanistic basis of these effects has been elusive because of difficulties in studying lipoprotein homeostasis in mice, which predominantly package circulating cholesterol in HDLs. Here, we tested the effects of OCA in chimeric mice whose livers are mostly composed (≥80%) of human hepatocytes. Chimeric mice exhibited a human-like ratio of serum LDL cholesterol (LDL-C) to HDL cholesterol (HDL-C) at baseline. OCA treatment in chimeric mice increased circulating LDL-C and decreased circulating HDL-C levels, demonstrating that these mice closely model the cholesterol effects of FXR activation in humans. Mechanistically, OCA treatment increased hepatic cholesterol in chimeric mice but not in control mice. This increase correlated with decreased SREBP-2 activity and target gene expression, including a significant reduction in LDL receptor protein. Cotreatment with atorvastatin reduced total cholesterol, rescued LDL receptor protein levels, and normalized serum LDL-C. Treatment with two clinically relevant nonsteroidal FXR agonists elicited similar lipoprotein and hepatic changes in chimeric mice, suggesting that the increase in circulating LDL-C is a class effect of FXR activation.

Abstract 50: A Phase I Clinical Trial Evaluating the Safety of With Allogeneic Adipose Tissue-derived Multilineage Progenitor Cells-transplantation Therapy in Homozygous Familial Hypercholesterolemia Patients

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Masahiro Koseki ◽  
Shizuya Yamashita
Keyword(s):  
Clinical Trial ◽  
Liver Transplantation ◽  
Adipose Tissue ◽  
Progenitor Cells ◽  
Familial Hypercholesterolemia ◽  
Ldl Cholesterol ◽  
Ldl Receptor ◽  
Ldl Apheresis ◽  
Definitive Therapy ◽  
Transplantation Therapy

Familial hypercholesterolemia (FH) is an inherited disorder, mainly caused by defects in low-density lipoprotein (LDL) receptor gene. The patients are characterized by high LDL cholesterol levels in the blood and premature cardiovascular disease. Although most of heterozygous FH patients are usually treated with statin, ezetimibe and bile acid sequestrants, homozygous FH patients are resistant to drug therapy. Therefore, in Japan, many of homozygous FH patients are treated by LDL-apheresis. LDL-apheresis is a great procedure to remove LDL cholesterol from the blood and contribute to improve prognosis of homozygous FH patients. However, the effect of removing LDL cholesterol is temporary and still not enough. As a definitive therapy, liver transplantation therapy could be one of options to recover LDL receptor, but donor is limited in Japan. Therefore, based on the increase of the evidence about the safety of mesenchymal stem cells and percutaneous transhepatic portal approach in islet transplantation, we have developed a cell transplantation therapy with allogeneic adipose tissue-derived multilineage progenitor cells (ADMPCs), as an alternative treatment instead of liver transplantation. Our group has already proved that xenogenic transplantation of human ADMPCs into Watanabe heritable hyperlipidemic rabbits resulted in significant reductions in total cholesterol, and the reductions were observed within 4 weeks and maintained for 12 weeks. These results suggested that hADMPC transplantation could correct the metabolic defects and be a novel therapy for inherited liver diseases. Here, we report a protocol for the first-in-human clinical trial, which has been approved by the institutional review board and Ministry of Health, Labour and Welfare, Japan.

Abstract 321: LRP6 Regulates LDL Receptor Internalization and LDL Uptake

2012 ◽  
Vol 32 (suppl_1) ◽  
Author(s):  
Arya Mani ◽  
Gwang-Woong Go ◽  
Zhi-jia Ye ◽  
Rajvir Singh
Keyword(s):  
Cho Cells ◽  
Ldl Cholesterol ◽  
Ldl Receptor ◽  
High Serum ◽  
Skin Fibroblasts ◽  
Receptor Internalization ◽  
Cholesterol Levels ◽  
Endocytic Machinery ◽  
Ldl Uptake

Genetic variations in LRP6 gene are associated with high serum LDL cholesterol levels and atherosclerosis. We examined the role of LRP6 in LDL receptor (LDLR) mediated LDL uptake. LDL uptake was increased when LRP6 was overexpressed and reduced when it was knocked down in LDLR deficient CHO cells. Interestingly, LRP6 knockdown in wildtype CHO cells resulted in a much greater decline in LDL uptake compared to ldlA7 cells. This finding suggested interaction between LRP6 and other proteins involved in LDL uptake. Strikingly, LDL receptor internalization was severely diminished when LRP6 was knocked down and was restored after LRP6 was reintroduced. Further investigations showed that LRP6 forms a complex with the LDL endocytic machinery including LDLR, clathrin and ARH and undergoes endocytosis after stimulation with LDL. LDLR internalization was defective in skin fibroblasts of the LRP6 R611C mutation carriers. LDLR and LRP6 internalizations as well as LDL uptake were significantly impaired in wildtype CHO cells expressing LRP6 R611C mutation(figa,b). These studies introduce LRP6 as a critical modulator of receptor-mediated LDL endocytosis and identify a mechanism by which variation in LRP6 may contribute to high serum LDL levels and atherosclerosis.

Abstract 203: Role of Glucagon Receptor Signalling in PCSK9 Regulation

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Stefano Spolitu ◽  
Lale Ozcan
Keyword(s):  
Lipid Metabolism ◽  
Blood Glucose ◽  
Ldl Cholesterol ◽  
Cholesterol Metabolism ◽  
Ldl Receptor ◽  
Receptor Protein ◽  
Obese Mice ◽  
Glucagon Receptor ◽  
Protein Levels ◽  
New Findings

Excessive glucagon receptor action in hepatocytes is a major contributing factor to type 2 diabetes (T2D). Accordingly, there has been great interest in developing glucagon receptor antagonists (GRAs) as a treatment for T2D. Although phase 2 clinical trials have shown that GRAs effectively lower blood glucose in T2D subjects, they increase plasma low density lipoprotein (LDL) cholesterol levels, which has presented a significant block to their development. In this context, recent studies have suggested that cholesterol and proprotein convertase subtilisin/kexin type 9 (PCSK9) levels can be regulated by fasting and perhaps glucagon, but in-depth mechanistic insight is lacking. In order to test the functional importance of hepatic glucagon action on lipid metabolism, we silenced glucagon receptor (GcgR) in obese mice using AAV8-H1-shGcgr to silence the receptor in hepatocytes. Consistent with previous reports, this treatment effectively lowered blood glucose in obese mice without a change in body weight. Moreover, GcgR silencing, like GRAs in humans, significantly increased plasma LDL cholesterol. In search for the mechanism, we found that inhibition of GcgR significantly lowered hepatic LDL-receptor protein levels and increased both hepatic PCSK9 and circulating PCSK9. To determine causation, we treated GcgR-silenced mice with a neutralizing monoclonal antibody against PCSK9 and found that this intervention restored hepatic LDL-receptor protein levels and prevented the increase in LDL cholesterol. Further mechanistic work revealed that GcgR silencing in hepatocytes did not increase Pcsk9 mRNA. Rather, blocking GcgR increased the half-life of PCSK9 protein by suppressing signalling through exchange protein activated by cAMP 1 (Epac1). In particular, the ability of GcgR silencing to increase PCSK9 and suppress LDL receptor protein levels was mimicked by hepatocytes lacking Epac1. Thus, GcgR signalling through Epac1 appears to have critical effects on processes that regulate cholesterol metabolism through PCSK9. These new findings have important implications for the lipid metabolism effects of hepatic glucagon signalling in both normal physiology and metabolic disease, and for the development of safer GRA-like drugs to treat T2D.

P6214How to improve long-term prevention in young patients after myocardial infarction - the IPP-Y study

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
H Wienbergen ◽  
T Retzlaff ◽  
J Erdmann ◽  
S Michel ◽  
L A Mata Marin ◽  
...  
Keyword(s):  
Risk Factors ◽  
Risk Factor ◽  
Randomized Trial ◽  
Prevention Program ◽  
Genetic Risk ◽  
Ldl Cholesterol ◽  
Young Patients ◽  
Risk Scores ◽  
Risk Factor Control

Abstract Background Patients who experienced myocardial infarction (MI) at a young age are of special medical and socioeconomic interest; cardiovascular risk factor control to prevent recurrent events is crucial in this specific cohort. Objectives The purpose of the study was to evaluate long-term risk factor control in young MI-patients in clinical practice and investigate the effects of a modern intensive prevention program in a prospective randomized trial. In a genetic substudy it was analyzed if prevention effects were depending on individual genetic risk. Methods Patients who had MI at age of ≤45 years were revisited after a mean period of 5.7±4.0 years to evaluate long-term risk factor control. Furthermore a 12-months intensive prevention program in young MI-patients (IPP-Y), coordinated by non-physician prevention assistants and including personal teachings, telephone contacts, clinical and telemetric control of risk factors, was compared to usual care in a randomized trial. Primary endpoint of the randomized trial was prevention success, defined as improvement of one of the risk factors smoking, LDL cholesterol or physical inactivity without deterioration of the others. As the opposite prevention failure was defined as deterioration of one of the risk factors without improvement of the others. Genetic risk was assessed by polygenetic risk scores, based on 163 SNPs. Results Only a minority of the 277 young patients after MI achieved guideline-recommended risk factor targets at long-term follow-up visits: mean body mass index was 29.9±5.1 kg/m2, just 14.8% had a body mass index <25 kg/m2. More than one third (38.3%) were persistent or recurrent smokers. Mean LDL cholesterol level was 94±38 mg/dl, only 27.1% of the patients achieved LDL cholesterol levels <70 mg/dl. However, the long-term prevention program IPP-Y led to a higher rate of the primary endpoint prevention success (IPP-Y: 49% vs. UC: 27%, p<0.05) and a lower rate of prevention failure (IPP-Y: 15% vs. UC: 38%, p<0.05) compared to usual care after 12 months (see figure). Telemetric control of risk factors as part of the prevention program was used by 71.4% of the patients. In the genetic subanalysis prevention effects were found in both, patients with high genetic risk as well as patients with low genetic risk assessed by polygenetic risk scores (p=0.79 high vs. low genetic risk). Effects of IPP-Y during 12 months Conclusions To our knowledge this is the first study on young patients with MI that demonstrates insufficient long-term risk factor control in clinical practice and significant effects of an intensive prevention program. Prevention effects were independent from individual genetic risk. Acknowledgement/Funding This work was supported by the Stiftung Bremer Herzen, Bremen, Germany and the Stiftung Bremer Wertpapierbörse, Bremen, Germany

Sign in / Sign up

Export Citation Format

Share Document