Substantial progress has been made in the application of lipidomics in biomarker discovery and drug development, as well as in a variety of other areas. In particular, the number of published studies reporting the quantitation and analysis of low-abundance lipid molecular species has greatly increased. It can be anticipated that many of the biochemical mechanisms underlying metabolic syndromes and other lipid-related diseases will be identified through these methods. Importantly, lipid markers evaluation of drug efficacy will be discovered as the ability to detect low-abundance lipid molecular species improves.
Inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) has been proposed to be a potential new therapeutic target for treatment of hypercholesterolaemia. However, little is known about the effects of PCSK9 inhibition on the lipidome. The study performed molecular lipidomic analyses of plasma samples obtained from PCSK9-deficient mice, and serum of human carriers of a loss-of-function variant in the PCSK9 gene (R46L).
In both mouse and man, PCSK9 deficiency caused a decrease in several cholesteryl esters (CE) and short fatty acid chain containing sphingolipid species such as CE 16:0, glucosyl/galactosylceramide (Glc/GalCer) d18:1/16:0, and lactosylceramide (LacCer) d18:1/16:0. In mice, the changes in lipid concentrations were most prominent when animals were given regular chow diet. In man, a number of molecular lipid species was shown to decrease significantly even when LDL-cholesterol was non-significantly reduced by 10% only. Western diet attenuated the lipid lowering potency of PCSK9 deficiency in mice.
Plasma molecular lipid species may be utilized for characterizing novel compounds inhibiting PCSK9 and as sensitive efficacy markers of the PCSK9 inhibition.
Fig1. Lipidomic biomarkers for drug efficacy (Jänis, Minna T.; et al, 2013)
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