Genomic Determinants of Triglyceride and Cholesterol Distribution into Lipoprotein Fractions in the Rat

Abstract

The plasma profile of major lipoprotein classes and its subdivision into particular fractions plays a crucial role in the pathogenesis of atherosclerosis and is a major predictor of coronary artery disease. Our aim was to identify genomic determinants of triglyceride and cholesterol distribution into lipoprotein fractions and lipoprotein particle sizes in the recombinant inbred rat set PXO, in which alleles of two rat models of the metabolic syndrome (SHR and PD inbred strains) segregate together with those from Brown Norway rat strain. Adult male rats of 15 PXO strains (n = 8–13/strain) and two progenitor strains SHR-Lx (n = 13) and BXH2/Cub (n = 18) were subjected to one-week of high-sucrose diet feeding. We performed association analyses of triglyceride (TG) and cholesterol (C) concentrations in 20 lipoprotein fractions and the size of major classes of lipoprotein particles utilizing 704 polymorphic microsatellite markers, the genome-wide significance was validated by 2,000 permutations per trait. Subsequent in silico focusing of the identified quantitative trait loci was completed using a map of over 20,000 single nucleotide polymorphisms. In most of the phenotypes we identified substantial gradient among the strains (e.g. VLDL-TG from 5.6 to 66.7 mg/dl). We have identified 14 loci (encompassing 1 to 65 genes) on rat chromosomes 3, 4, 7, 8, 11 and 12 showing suggestive or significant association to one or more of the studied traits. PXO strains carrying the SHR allele displayed significantly higher values of the linked traits except for LDL-TG and adiposity index. Cholesterol concentrations in large, medium and very small LDL particles were significantly associated to a haplotype block spanning part of a single gene, low density lipoprotein receptor-related protein 1B (Lrp1b). Using genome-wide association we have identified new genetic determinants of triglyceride and cholesterol distribution into lipoprotein fractions in the recombinant inbred panel of rat model strains.

Genome-wide association study of coronary artery calcified atherosclerotic plaque in African Americans with type 2 diabetes

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Genetic determinants of pig birth weight variability

“…Dietrich et al [ 55 ] reported that knockout of Lrp1b in mice results in early embryonic lethality. Association analysis identified LRP1B as a determinant of rat cholesterol concentrations in LDL, and a significant association with child body mass index (BMI) in human [ 56 , 57 ]. Furthermore, recent studies suggested the LRP1B gene was also involved in glucose homeostasis.…”

Ellagic Acid Affects Metabolic and Transcriptomic Profiles and Attenuates Features of Metabolic Syndrome in Adult Male Rats

“…The serum lipid profile was assessed using gel-permeation high-performance liquid chromatography at Skylight Biotech Inc. (Akita, Japan) allowing simultaneous quantification of cholesterol and triacylglycerols in 20 lipoprotein subfractions as described previously [ 29 , 30 ]. In short, a three-step method was utilized, including the loading of sample into a gel permeation column followed by elution of lipoproteins in decreasing order of size, feeding them into reaction coils; the products were registered by detectors and the levels of triacylglycerols and cholesterol in the individual lipoprotein fractions were obtained in the form of composite chromatogram.…”