Errata. PCSK9 function and physiology

Abstract

PCSK9 has exploded onto center stage of plasma cholesterol metabolism, raising hopes for a new strategy to treat hypercholesterolemia. PCSK9 in a plasma protein that triggers increased degradation of the LDL receptor. Gainof-function mutations in PCSK9 reduce LDL receptor levels in the liver, resulting in high levels of LDL cholesterol in the plasma and increased susceptibility to coronary heart disease. Loss-of-function mutations lead to higher levels of the LDL receptor, lower LDL cholesterol levels, and protection from coronary heart disease. Two papers in this issue of the Journal of Lipid Research exemplify the rapid pace of progress in understanding PCSK9 molecular interactions and physiology. Dr. Shilpa Pandit and coworkers from Merck Research Laboratories describe the functional basis for the hypercholesterolemia associated with gain-offunction missense mutations in PCSK9. Dr. Jay Horton's group at UT Southwestern describe the kinetics and metabolism of PCSK9 and the impact of PCSK9 on LDL receptors in the liver and adrenal gland. During the past few years, the proprotein convertase subtilisin kexin 9 (PCSK9) field has been red hot, fueled by the realization that PCSK9 is a key player in plasma cholesterol metabolism and by a hope, shared by scientists in academia and industry alike, that PCSK9 is a target for treating hypercholesterolemia. PCSK9 regulates the levels of the LDL receptor (1-3), which is a plasma membrane glycoprotein that removes cholesterol-rich LDL particles from the plasma (4, 5). Gain-of-function mutations in PCSK9 reduce LDL receptor levels in the liver, resulting in high levels of LDL cholesterol in the plasma and increased susceptibility to coronary heart disease (6). Loss-of-function mutations lead to higher levels of the LDL receptor, lower LDL cholesterol levels, and protection from coronary heart disease (7-11). The loss of PCSK9 appears to have no adverse consequences (11). Thus, interest in PCSK9 as a cholesterol-lowering target has been high, and an army of investigators is now working to elucidate PCSK9 molecular interactions and physiology. In this issue of the Journal of Lipid Research ( JLR), two leading research groups describe their recent efforts. Dr. Shilpa Pandit et al. (12) from Merck Research Laboratories describe the functional basis for the hypercholesterolemia associated with gain-of-function missense mutations in PCSK9. Grefhorst et al. (13) at UT Southwestern describe the kinetics and metabolism of recombinant PCSK9 and the impact of PCSK9 on LDL receptors in the liver and adrenal gland.PCSK9 was initially identified as a new member of the proprotein convertase family and suggested to have a role in liver regeneration and the differentiation of cortical neurons (14). Its relevance to cholesterol metabolism was suggested by a pair of unrelated observations. The first was the discovery, by Abifadel et al. (6), that heterozygosity for specific PCSK9 missense mutations cause autosomal dominant hypercholesterolemia. For most enzymes, the loss of a single ...

Effects of a New Nutraceutical Formulation (Berberine, Red Yeast Rice and Chitosan) on Non-HDL Cholesterol Levels in Individuals with Dyslipidemia: Results from a Randomized, Double Blind, Placebo-Controlled Study

“…The recent development of the plasma proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors has highlighted the importance of PCSK9 as a new therapeutic target for lowering LDL-C and dyslipidemia-associated CV disease (CVD) [ 9 ]. PCSK9 is a liver protease which promotes hepatic LDL receptor degradation with consequent reduction in LDL receptor density and uptake and LDL clearance, with increased LDL-C levels [ 10 ]. Emerging evidence demonstrated that statin therapy is associated with an undesirable significant increase in plasma PCSK9 irrespective of type of statin and treatment duration, and that its combination therapy with ezetimibe may further increase PCSK9 compared to statin alone, thus blunting lipid-lowering and cardioprotective actions of statins, and, perhaps of ezetimibe [ 11 ].…”

Evaluating the Holdup Time of Gas-Chromatographic Systems in Various Temperature Regimes by Using Recurrent Relations

“…Really it unites the methods based both on the linearization of the dependence (3) and the algorithm proposed by Peterson and Hirsch [10] that can be confirmed by the following comments:…”

“…Such exhaustive complexity de facto restricts the use of the corresponding algorithms in analytical practice. Just due to this reason, the simplest method of Peterson and Hirsch [10] (Eq. 5) retains its importance up to the present.…”

“…This fact should be taken into account as the main criterion of the usefulness of any algorithms of t 0 precalculation: they can be accepted only at the maximal simplicity of the calculations. Hence, it is not surprising that historically the first approach proposed as early as 1959 (Peterson and Hirsch method) [10] (some of its modifications [11,12] are known) has received the most popularity. The evaluation of t 0 at isothermal conditions of GC analysis requires the values of retention times of three consecutive homologues:…”

Determination and evaluation of gas holdup time with the quadratic equation model and comparison with nonlinear models for isothermal gas chromatography

“…Many calculation methods have been proposed based on the linear equation (LE) model. Peterson and Hirsch [19] proposed to use retention times of three members in a homologous series to calculate the t M value. Since then, a large number of papers and reviews have been published [8,20–23], among which the method proposed by Guardino et al [24] has been well accepted to obtain a t M value denoted with t MM .…”