scholarly journals SUN-574 A1AT: Novel Inhibitor of Active PCSK9

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Quantil Melendez ◽  
Catherine Wooten ◽  
Sumaira Ahmed ◽  
Ariel Renee’ Williams ◽  
Kevin Sean Kimbro ◽  
...  
Keyword(s):  
Heart Disease ◽  
Ldl Cholesterol ◽  
Metabolic Diseases ◽  
Cholesterol Metabolism ◽  
Ldl Receptor ◽  
Response Analysis ◽  
Statin Intolerance ◽  
Receptor Complexes ◽  
Cholesterol Levels

Abstract Heart disease is the principal cause of death and disability for both men and women in the US, accounting for 40% of all annual deaths. African American populations are disproportionately burdened with metabolic diseases, due in part to cholesterol metabolism deficiencies. Elevated low density lipoprotein (LDL) cholesterol levels and inflammation promote atherogenic conditions which lead to heart disease. Proprotein convertase subtilisin/kexin-9 (PCSK9) is a biomarker which enhances athrogenic progression by controlling the number of LDL receptor molecules expressed at the plasma membrane. PCSK9 indirectly regulates LDL-cholesterol levels. Previous reports show some patients do not respond well to general anti-cholesterolemic treatments. We believe this is due to altered PCSK9 activity, which is currently not being evaluated. We have developed a novel assay to detect active PCSK9. A1AT is a SERPIN family member whose primary objective is inhibition of proteases. Specific levels of A1AT are required to maintain metabolic homeostasis. Based on this, we hypothesized that a specific ratio between A1AT serum levels and PCSK9 activity levels would eliminate statin intolerance/resistance, regulating LDL-cholesterol metabolism congruently. Using this novel active PCSK9 detection assay, we provide evidence that A1AT interacts with PCSK9 in the medium of C3A hepatic-like cells, preventing the formation of PCSK9/LDL receptor complexes in vitro. There was an approximate 20% inhibition in PCSK9-LDL receptor complex formation when liver cells were treated with recombinant A1AT (rA1AT). A dose dependent response analysis proved 200ng/ml of rA1AT had an 46% reduction in PCSK9 activity. We determined PCSK9 activty and A1AT levels correlate with key diabetic factors in humans, suggesting that A1AT could effect diabetes progression.

scholarly journals GOLIATH regulates LDLR availability and plasma LDL cholesterol levels

2020 ◽  
Author(s):  
Bethan L. Clifford ◽  
Kelsey E. Jarrett ◽  
Joan Cheng ◽  
Angela Cheng ◽  
Marcus Seldin ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Ldl Cholesterol ◽  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Lipoprotein Receptors ◽  
Cholesterol Levels ◽  
Genome Wide

AbstractIncreasing the availability of hepatic low-density lipoprotein receptors (LDLR) remains a major clinical target for reducing circulating plasma LDL cholesterol (LDL-C) levels. Here, we identify the molecular mechanism underlying genome-wide significant associations in the GOLIATH locus with plasma LDL-C levels. We demonstrate that GOLIATH is an E3 ubiquitin ligase that ubiquitinates the LDL Receptor resulting in redistribution away from the plasma membrane. Overexpression of GOLIATH decreases hepatic LDLR and increases plasma LDL-C levels. Silencing of Goliath using antisense oligonucleotides, germline deletion, or AAV-CRISPR in vivo strategies increases hepatic LDLR abundance and availability, thus decreasing plasma LDL-C. In vitro ubiquitination assays demonstrate RING-dependent regulation of LDLR abundance at the plasma membrane. Our studies identify GOLIATH as a novel post-translational regulator of LDL-C levels via modulation of LDLR availability, which is likely important for understanding the complex regulation of hepatic LDLR.

scholarly journals HSP25 Vaccination Attenuates Atherogenesis via Upregulation of LDLR Expression, Lowering of PCSK9 Levels and Curbing of Inflammation

2021 ◽  
Author(s):  
Yong-Xiang Chen ◽  
Chunhua Shi ◽  
Jingti Deng ◽  
Catherine Diao ◽  
Nadia Maarouf ◽  
...  
Keyword(s):  
Protein Expression ◽  
Immune Complex ◽  
Cholesterol Metabolism ◽  
Plaque Burden ◽  
Blood Levels ◽  
Igg Antibodies ◽  
Amyloid A ◽  
Cholesterol Levels ◽  
Mrna And Protein Expression

Objective: Elevated HSP27 (heat shock protein 27) levels predict relative freedom from cardiovascular events. Over-expression or twice daily subcutaneous injections of human HSP27 in ApoE −/− mice reduces blood and plaque cholesterol levels, as well as inflammation and atherosclerotic plaque burden. Antibodies to HSP27 are present in human blood, and the purpose of the current studies is to explore their role. Approach and Results: Blood levels of both HSP27 and anti-HSP27 IgG antibodies are elevated in healthy controls compared with patients with cardiovascular disease. ApoE −/− mice fed a high-fat diet and vaccinated with recombinant HSP25 (rHSP25, murine ortholog) show increased levels of anti-HSP25 IgG antibodies and reductions in plasma cholesterol and atherogenesis. Moreover, rHSP25 vaccination markedly lowered serum amyloid A levels as well as hepatic macrophage abundance and inflammatory cytokine expression. The effects of the HPS25 vaccination on cholesterol metabolism are divergent: increased hepatic LDLR (low-density lipoprotein receptor) mRNA and protein expression and reduced plasma PCSK9 (proprotein convertase subtilisin/kexin type 9) levels—despite no effect on PCSK9 expression. In vitro, the HSP27 immune complex upregulates hepatocyte LDLR mRNA and protein expression independent of intracellular cholesterol levels and increases LDLR promoter activity. The increase in LDLR expression by the HSP27 immune complex is dependent upon activation of the NF-κB (nuclear factor κ light chain enhancer of activated B cells) pathway. Hepatocyte PCSK9 protein levels are reduced after HSP27 immune complex treatment in vitro despite only minor transient effects on gene expression. Conclusions: HSP27 immunotherapy represents a novel means of lowering cholesterol and PCSK9 levels, primarily due to augmentation of LDLR expression and is associated with marked reductions in inflammation.

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.

scholarly journals Cholesterol Levels in Genetically Determined Familial Hypercholesterolaemia in Russian Karelia

Cholesterol ◽  
2017 ◽  
Vol 2017 ◽  
pp. 1-6 ◽  
Author(s):  
V. A. Korneva ◽  
T. Yu. Kuznetsova ◽  
T. Yu. Bogoslovskaya ◽  
D. S. Polyakov ◽  
V. B. Vasilyev ◽  
...  
Keyword(s):  
Ldl Cholesterol ◽  
Familial Hypercholesterolaemia ◽  
Receptor Gene ◽  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Gene Mutations ◽  
Density Lipoprotein ◽  
Single Strand Conformation Polymorphism ◽  
Polymorphism Analysis ◽  
Cholesterol Levels

Familial hypercholesterolaemia (FH) is a rare disease that tends to be diagnosed lately. In Russia, the genetic and phenotypic characteristics of the disease are not well defined. We investigated 102 patients with definite FH. In 52 of these patients (50.9%) genetic analysis was performed, revealing pathogenic mutations of the low density lipoprotein (LDL) receptor gene in 22 patients. We report here five mutations of the LDL receptor gene found in the Karelian FH sample for the first time. The detection rate of mutations in definite FH patients was 42.3%. Two groups of patients with a definite diagnosis of FH according to the Dutch Lipid Clinic Network criteria were compared: the first group had putatively functionally important LDL receptor gene mutations, while in the second group LDL receptor gene mutations were excluded by single-strand conformation polymorphism analysis. Total and LDL cholesterol levels were higher in the group with LDL receptor mutations compared to the mutation-free population. The frequency of mutations in patients with LDL cholesterol > 6.5 mmol/L was more than 3 times higher than that in patients with LDL < 6.5 mmol/L. Total and LDL cholesterol levels and the frequency of coronary heart disease and myocardial infarction were higher in the group with definite FH compared to groups with probable and possible FH. Cholesterol figures in FH patients of different age and sex from the Karelian population were comparable.

scholarly journals The usual dosage regimen of statins and adherence to target LDL-cholesterol levels by Czech patients in the secondary prevention of coronary heart disease

Cor et Vasa ◽  
2009 ◽  
Vol 51 (2) ◽  
pp. 92-96 ◽  
Author(s):  
Otto Mayer ◽  
Jaroslav Šimon ◽  
Jan Bruthans ◽  
Markéta Galovcová ◽  
Jana Hrbková ◽  
...  
Keyword(s):  
Coronary Heart Disease ◽  
Heart Disease ◽  
Secondary Prevention ◽  
Dosage Regimen ◽  
Ldl Cholesterol ◽  
Cholesterol Levels ◽  
Usual Dosage

scholarly journals The Description of Low Density Lipoprotein (LDL) Levels on Smoker and Non Smoker Adolescent in Buyan Hamlet, Pancasari Village, Sukasada District, Buleleng, Bali

2017 ◽  
Vol 4 (1) ◽  
pp. 39-44
Author(s):  
Ni Made Restina Juliani ◽  
I Putu Oka Dharmawan ◽  
Putu Ayu Parwati
Keyword(s):  
Physical Activity ◽  
Coronary Heart Disease ◽  
Heart Disease ◽  
Ldl Cholesterol ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
The Body ◽  
Low Density ◽  
Blood Samples ◽  
Cholesterol Levels

Introduction: Low Density Lipoprotein (LDL) is a type of low-density lipoprotein and the most widely transported cholesterol in the body. Increased levels of LDL in the body can be affected by genetics, age, gender, obesity, physical activity, lifestyle, drug consumption and smoking. Substances in a cigarette can cause an increase of LDL levels. Increased of LDL cholesterol levels can cause Coronary Heart Disease (CHD). The purpose of this research is to know the description of Low Density Lipoprotein (LDL) levels on smoker and non-smoker adolescent in Buyan Hamlet, Pancasari Village, Sukasada District, Buleleng Bali. Method: The type of this research is descriptive. This research was conducted in April-May 2017, which used fasting blood samples of 42 respondents. Result: From the average result of LDL level in smoker adolescent that is 134,91 mg/dL higher than the average of LDL level in non-smoker adolescent that is 74,90 mg/dL. The result of LDL cholesterol levels was determined by 21 smoker adolescent respondents with the close to optimal category (100-129 mg/dL) as many as 9 people (42,8%), and 12 people (57,3%) with worry category (130-159 mg/dL). Whereas in 21 non-smoker adolescent respondents obtained  result of LDL cholesterol level test with optimal category (<100 mg/dL) counted 18 people (87,71%) and 3 person (14,30%) with close to optimal category (100-129 mg/dL). Discussion: Based on the results of this research can be concluded that in smoker adolescent obtained LDL levels with close to optimal category and worrying whereas in non-smoker adolescents obtained LDL levels in the optimal category and close to optimal.

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