Insights Into PCSK9, Low-Density Lipoprotein Receptor, and Low-Density Lipoprotein Cholesterol Metabolism

Stein, Evan A.; Raal, Frederick J.

doi:10.1161/circulationaha.113.003360

Cited by 24 publications

(16 citation statements)

References 12 publications

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“…Statins activate LDL receptor (LDLR) gene expression, but also activate the expression of proprotein convertase subtilisin/kexin type 9 (PCSK9), a secreted inhibitor of LDLR, thereby limiting their beneficial effects [68]. PCSK9 is a serine protease expressed predominantly in the liver, intestine and kidney [69]. PCSK9 directly binds to the epidermal growth factor-like repeat A domain of the LDL receptor and induces its degradation, thereby controlling circulating LDL-C concentration [70, 71].…”

Section: Lipid Update 2013mentioning

confidence: 99%

Lipid, blood pressure and kidney update 2013

et al. 2014

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The year 2013 proved to be very exciting as far as landmark trials and new guidelines in the field of lipid disorders, blood pressure and kidney diseases. Among these are the International Atherosclerosis Society Global Recommendations for the Management of Dyslipidemia, European Society of Cardiology (ESC)/European Society of Hypertension Guidelines for the Management of Arterial Hypertension, American Diabetes Association Clinical Practice Recommendations, the Kidney Disease: Improving Global Outcomes Clinical Practice Guidelines for Managing Dyslipidemias in Chronic Kidney Disease (CKD) Patients, the American College of Cardiology/American Heart Association Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults, the Joint National Committee Expert Panel (JNC 8) Evidence-Based Guideline for the Management of High Blood Pressure in Adults, the American Society of Hypertension/International Society of Hypertension Clinical Practice Guidelines for the Management of Hypertension in the Community, the American College of Physicians Clinical Practice Guideline on Screening, Monitoring, and Treatment of Stage 1–3 CKD and many important trials presented among others during the ESC Annual Congress in Amsterdam and the American Society of Nephrology Annual Meeting—Kidney Week in Atlanta, GA. The paper is an attempt to summarize the most important events and reports in the mentioned areas in the passing year.

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Section: Lipid Update 2013mentioning

confidence: 99%

Lipid, blood pressure and kidney update 2013

et al. 2014

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“…We have recently shown that PCSK9 increases systemic inflammation and organ failure during infection by reducing the hepatic clearance of bacterial endotoxins via the LDL receptor [1]. Produced and secreted from the liver, production of PCSK9 is normally tightly orchestrated via SREBP transactivation of the PCSK9 promoter region [2]. SREBP transcription factors are cleaved and translocate to the nucleus when there are low levels of cholesterol-derived sterols.…”

Section: Introductionmentioning

confidence: 99%

Increased Plasma PCSK9 Levels Are Associated with Reduced Endotoxin Clearance and the Development of Acute Organ Failures during Sepsis

Boyd¹,

Fjell²,

Russell³

et al. 2016

J Innate Immun

118

110

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Purpose: We have recently shown that PCSK9 reduces the clearance of endotoxin and is therefore a critical regulator of the innate immune response during infection. However, plasma PCSK9 levels during human sepsis and their relationship to outcomes are not known. Our objective was to determine the relationship between plasma PCSK9 levels and the rate of endotoxin clearance, and then correlate PCSK9 levels with the development of acute organ failures in a cohort of patients with sepsis. Methods: Using human hepatocyte cells, we determined the threshold at which PCSK9 is able to reduce Escherichia coli endotoxin uptake by cultured human hepatocytes. In a single-centre observational cohort at St. Paul's Hospital in Vancouver, Canada, we recruited 200 patients who activated our Emergency Department's sepsis protocol and measured plasma PCSK9 and lipid levels at triage and throughout the admission. Outcomes were the development of sepsis-induced cardiovascular or respiratory failure. Results: We reviewed the literature and determined that the normal human range of PCSK9 found in plasma is 170-220 ng/ml, while levels of 250 ng/ml and above reduced E. coli endotoxin clearance in cultured human hepatocytes. In septic patients, the median levels associated with new-onset respiratory and cardiovascular failure were 370 (250-500) and 380 (270-530) ng/ml, respectively, versus 270 (220-380) ng/ml in patients who did not go on to develop any organ failure (p = 0.003 and 0.005, respectively). Conclusions: Plasma PCSK9 levels are greatly increased in sepsis. At normal levels, PCSK9 has no influence upon hepatocyte bacterial endotoxin clearance, but as levels rise, there is a progressive inhibition of clearance. During sepsis, PCSK9 levels are highly correlated with the development of subsequent multiple organ failure. Inhibition of PCSK9 activity is an attractive target for treating the spectrum of sepsis and septic shock.

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“…Monoclonal antibodies (mAbs) that block PCSK9 have been recently approved for clinical use in Europe and the US as a treatment for severe hypercholesterolemia 19 . PCSK9 inhibition reduces LDL-C levels by up to 65%, mainly by increasing hepatic LDLR levels and increasing the efficiency of clearance of LDL particles 20 . PCSK9 inhibition also reduces Lp(a) levels by up to 35% in a dose-dependent manner through an unexplained mechanism 21 .…”

Section: Introductionmentioning

confidence: 99%

PCSK9 Association With Lipoprotein(a)

Tavori

Christian

Minnier

et al. 2016

Circulation Research

101

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Rationale Lipoprotein(a) [Lp(a)] is a highly atherogenic low-density lipoprotein (LDL)-like particle characterized by the presence of apoprotein(a) [apo(a)] bound to apolipoprotein B (apoB). Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) selectively binds LDL, we hypothesized that it can also be associated with Lp(a) in plasma. Objective Characterize the association of PCSK9 and Lp(a) in 39 subjects with high Lp(a) levels (range 39-320 mg/dl) and in transgenic mice expressing either human apo(a) only or human Lp(a) (via co-expression of human apo(a) and human apoB). Methods and Results We show that PCSK9 is physically associated with Lp(a) in vivo using three different approaches: (i) Analysis of Lp(a) fractions isolated by ultracentrifugation; (ii) Immunoprecipitation of plasma using antibodies to PCSK9 and immunodetection of apo(a); (iii) ELISA quantification of Lp(a)-associated PCSK9. Plasma PCSK9 levels correlated with Lp(a) levels, but not with the number of kringle IV-2 repeats. PCSK9 did not bind to apo(a) only and the association of PCSK9 with Lp(a) was not affected by the loss of the apo(a) region responsible for binding oxidized phospholipids. Preferential association of PCSK9 with Lp(a) vs. LDL (1.7-fold increase) was seen in subjects with high Lp(a) and normal LDL. Finally, Lp(a)-associated PCSK9 levels directly correlated with plasma Lp(a) levels but not with total plasma PCSK9 levels. Conclusions Our results show, for the first time, that plasma PCSK9 is found in association with Lp(a) particles in humans with high Lp(a) levels and in mice carrying human Lp(a). Lp(a)-bound PCSK9 may be pursued as a biomarker for cardiovascular risk.

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Insights Into PCSK9, Low-Density Lipoprotein Receptor, and Low-Density Lipoprotein Cholesterol Metabolism

Cited by 24 publications

References 12 publications

Lipid, blood pressure and kidney update 2013

Lipid, blood pressure and kidney update 2013

Increased Plasma PCSK9 Levels Are Associated with Reduced Endotoxin Clearance and the Development of Acute Organ Failures during Sepsis

PCSK9 Association With Lipoprotein(a)

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