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Lipoprotein signatures of cholesteryl ester transfer protein and HMG-CoA reductase inhibition.

07:00 EST 20th December 2019 | BioPortfolio

Summary of "Lipoprotein signatures of cholesteryl ester transfer protein and HMG-CoA reductase inhibition."

Cholesteryl ester transfer protein (CETP) inhibition reduces vascular event risk, but confusion surrounds its effects on low-density lipoprotein (LDL) cholesterol. Here, we clarify associations of genetic inhibition of CETP on detailed lipoprotein measures and compare those to genetic inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR). We used an allele associated with lower CETP expression (rs247617) to mimic CETP inhibition and an allele associated with lower HMGCR expression (rs12916) to mimic the well-known effects of statins for comparison. The study consists of 65,427 participants of European ancestries with detailed lipoprotein subclass profiling from nuclear magnetic resonance spectroscopy. Genetic associations were scaled to 10% reduction in relative risk of coronary heart disease (CHD). We also examined observational associations of the lipoprotein subclass measures with risk of incident CHD in 3 population-based cohorts totalling 616 incident cases and 13,564 controls during 8-year follow-up. Genetic inhibition of CETP and HMGCR resulted in near-identical associations with LDL cholesterol concentration estimated by the Friedewald equation. Inhibition of HMGCR had relatively consistent associations on lower cholesterol concentrations across all apolipoprotein B-containing lipoproteins. In contrast, the associations of the inhibition of CETP were stronger on lower remnant and very LDL (VLDL) cholesterol, but there were no associations on cholesterol concentrations in LDL defined by particle size (diameter 18-26 nm) (-0.02 SD LDL defined by particle size; 95%
CI:
-0.10 to 0.05 for CETP versus -0.24 SD, 95% CI -0.30 to -0.18 for HMGCR). Inhibition of CETP was strongly associated with lower proportion of triglycerides in all high-density lipoprotein (HDL) particles. In observational analyses, a higher triglyceride composition within HDL subclasses was associated with higher risk of CHD, independently of total cholesterol and triglycerides (strongest hazard ratio per 1 SD higher triglyceride composition in very large HDL 1.35; 95%
CI:
1.18-1.54). In conclusion, CETP inhibition does not appear to affect size-specific LDL cholesterol but is likely to lower CHD risk by lowering concentrations of other atherogenic, apolipoprotein B-containing lipoproteins (such as remnant and VLDLs). Inhibition of CETP also lowers triglyceride composition in HDL particles, a phenomenon reflecting combined effects of circulating HDL, triglycerides, and apolipoprotein B-containing particles and is associated with a lower CHD risk in observational analyses. Our results reveal that conventional composite lipid assays may mask heterogeneous effects of emerging lipid-altering therapies.

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Journal Details

This article was published in the following journal.

Name: PLoS biology
ISSN: 1545-7885
Pages: e3000572

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Medical and Biotech [MESH] Definitions

A lipoprotein that resembles the LOW-DENSITY LIPOPROTEINS but with an extra protein moiety, APOPROTEIN (A) also known as APOLIPOPROTEIN (A), linked to APOLIPOPROTEIN B-100 on the LDL by one or two disulfide bonds. High plasma level of lipoprotein (a) is associated with increased risk of atherosclerotic cardiovascular disease.

An abnormal lipoprotein present in large amounts in patients with obstructive liver diseases such as INTRAHEPATIC CHOLESTASIS. LP-X derives from the reflux of BILE lipoproteins into the bloodstream. LP-X is a low-density lipoprotein rich in free CHOLESTEROL and PHOSPHOLIPIDS but poor in TRIGLYCERIDES; CHOLESTEROL ESTERS; and protein.

A superfamily of large integral ATP-binding cassette membrane proteins whose expression pattern is consistent with a role in lipid (cholesterol) efflux. It is implicated in TANGIER DISEASE characterized by accumulation of cholesteryl ester in various tissues.

An ester of nicotinic acid that lowers cholesterol and triglycerides in total plasma and in the VLD- and LD-lipoprotein fractions.

Compounds that increase the enzymatic activity of LIPOPROTEIN LIPASE. Lipoprotein lipase activators have a potential role in the treatment of OBESITY by increasing LIPID METABOLISM. Note that substances that increase the synthesis of lipoprotein lipase are not included here.

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