Statins, plasma proprotein convertase subtilisin/kexin type 9 concentrations, and LDL lowering.
نویسنده
چکیده
The discovery in 2003 that variants in the PCSK9 (proprotein convertase subtilisin/kexin type 9) gene cause autosomal dominant hypercholesterolemia revealed a new aspect of LDL cholesterol (LDL-C) metabolism (1). PCSK9, a protein of 692 amino acid residues produced at high concentrations in the liver, kidney, and intestine, has profound effects on LDL-C concentrations (2). Both gain-of-function and loss-of-function PCSK9 variants that cause higher and lower LDL-C concentrations, respectively, have been described, and variants in PCSK9 contribute to population variation in LDL-C values (3). The mechanism by which PCSK9 affects LDL-C concentrations involves direct binding of the protein to epidermal growth factor–like repeat A in the extracellular domain of the LDL receptor (LDLR), thereby accelerating degradation of the receptor (4). PCSK9 is a secreted protein that circulates in the blood. Several ELISA assays have been developed to measure PCSK9 concentrations (5, 6 ) and relate them to various biological correlates and differences in response to therapy, which may have implications for the therapeutic targeting of this protein. The interactions of statins with PCSK9 are of great interest, not only because statins are the predominant therapeutic agents used to decrease LDL-C but also because both the LDLR and PCSK9 share a common transcriptional regulator, sterol regulator element– binding protein 2 (SREBP-2) (7 ). Statin exposure produces an increase in the concentrations of both LDLR and PCSK9 mRNAs. The upregulation of PCSK9, which promotes the degradation of the LDLR, serves as a counterregulatory molecular brake on LDL-C lowering. The study described by Awan et al. (8 ) in this issue of Clinical Chemistry examines the relationship between plasma PCSK9 and LDL-C lowering in patients treated with statins in the JUPITER (Justification for Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin) trial. This clinical trial included apparently healthy participants with concentrations of LDL-C 130 mg/dL ( 3.4 mmol/L) and highsensitivity C-reactive protein 2.0 mg/L randomized to either 20 mg rosuvastatin or placebo. A random sample of 500 men and 500 women allocated equally to each treatment group were selected for measurement of LDL-C and PCSK9 concentrations. A modest correlation was found between baseline PCSK9 and LDL-C concentrations (r 0.15; P 0.0001). No association between these markers was found after statin treatment. Finally, a modest inverse correlation was apparent between the percentage change in PCSK9 concentrations and the change in LDL-C values (r 0.15; P 0.0005) for those on rosuvastatin treatment. Several other groups have found a modest correlation between untreated PCSK9 and LDL-C concentrations (5, 6, 9, 10) that likely reflects coordinated upregulation of the LDLR and PCSK9 by SREBP-2 in response to higher cholesterol concentrations. The magnitude of the correlation between PCSK9 values and plasma LDL-C concentrations has been less than expected. Several factors may contribute to the low level of correlation between these 2 variables. First, the ELISA assays used to measure PCSK9 were able to capture only a subset of the circulating protein. Second, PCSK9 may bind to proteins and lipoproteins that affect its clearance. Currently, it is not known how PCSK9 is cleared from the circulation in humans. Third, there are significant diurnal changes in PCSK9, and PCSK9 concentrations are reduced with fasting (up to 58% lower after 36 h of fasting) (11, 12). Despite wide fluctuations in plasma PCSK9 concentrations over the course of a day, there is little diurnal variation in plasma LDL-C. Thus, additional factors must contribute to the relationship between plasma PCSK9 and LDL-C concentrations. These same variability issues may also contribute to the very modest inverse correlation found in the JUPITER study (r 0.15) between the ontreatment change in LDL-C and the change in PCSK9. Others have reported this correlation to be either negligible (r 0.05) (10) or of a magnitude similar to that reported in this study (9). Importantly, in the setting of statin treatment, statin dosing and concentrations may be more important determinants of PCSK9 than LDL-C concentrations, especially given the potent effects of sta1 Donald W. Reynolds Cardiovascular Clinical Research Center and Division of Cardiology, University of Texas Southwestern Medical Center, Dallas, TX. * Address correspondence to the author at: UT Southwestern Medical Center, 5909 Harry Hines Blvd., HA 9.133, Dallas, TX 75390-9047. Fax 214-645-7501; e-mail [email protected]. Received October 25, 2011; accepted October 26, 2011. Previously published online at DOI: 10.1373/clinchem.2011.176800 2 Nonstandard abbreviations: LDL-C, LDL cholesterol; LDLR, LDL receptor; SREBP-2, sterol regulator element–binding protein 2; JUPITER, Justification for Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (trial). Clinical Chemistry 58:1 6–7 (2012) Editorials
منابع مشابه
PCSK9 (Proprotein convertase subtilisin/kexin type 9) inhibitors: past, present, and the future.
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ورودعنوان ژورنال:
- Clinical chemistry
دوره 58 1 شماره
صفحات -
تاریخ انتشار 2012