The association between LRP-1 variants and chylomicron uptake after a high fat meal

Abstract

Background and aims In vitro studies suggest that low density lipoprotein receptor-related protein 1 (LRP1) plays a role in the secondary uptake of chylomicrons. In addition, in vivo studies using LRP-1 knockout mice show these animals exhibit delayed chylomicron clearance. Whether this is true in humans is unknown. We aimed to determine whether genetic variants in LRP-1 are associated with postprandial chylomicron uptake in humans given an oral fat challenge. Methods and Results 817 Men and women (mean age +/− standard deviation = 48.4 +/− 16.4 years) forming the study population for the Genetics of Lipid Lowering Drugs Network (GOLDN) study ingested an oral fat load of 700 kilocalories per m2 of body surface area at 83% fat, after an 8-hour fast. Chylomicrons were measured by nuclear resonance spectroscopy (NMR) at fasting, and 3.5 and 6 hours after the meal. 26 Single nucleotide polymorphisms (SNPs) in the LRP-1 gene were genotyped on the Affymetrix 6.0 array. Chylomicrons were, as expected, zero at fasting. Mixed linear models adjusted for age, sex, study site and pedigree tested for associations between LRP-1 SNPs and changes in chylomicron concentrations 3.5–6 hours. A gene-based test across all 26 SNPs was conducted which corrected for the linkage disequilibrium (LD) between SNPs. 11 LRP-1 SNPs were significantly associated with the change in chylomicron concentration correction for multiple testing (Q<.05). The subsequent gene-based test, was also significant (P= .01). Conclusion These results require replication but strongly indicate the role of LRP1 in postprandial lipoprotein uptake and/or clearance.

Postprandial triglyceride-rich lipoproteins promote lipid accumulation and apolipoprotein B-48 receptor transcriptional activity in human circulating and murine bone marrow neutrophils in a fatty acid-dependent manner

“…Similar results have been found in ApoB48R-SiRNA-transfected THP-1 monocytes [28]. LRP-1, which may be involved in the secondary uptake and/or clearance of postprandial lipoproteins by the liver in humans [29], did not increase in control shRNAcc-transfected neutrophils after TRL stimulation regarding the fact that intracellular TGs accumulated in those cells. Similarly, LRP-1 mRNA expression levels were down-regulated in circulating monocytes at the postprandial phase in response to a high-fat meal [11].…”

Familial Hypercholesterolemia: The Most Frequent Cholesterol Metabolism Disorder Caused Disease

“…Hydrolysis of FFAs from chylomicrons results in smaller particles enriched in cholesterol esters that transfer ApoA and ApoC to other lipoproteins (basically high density lipoproteins (HDL)) and acquire ApoE [ 33 ]. Finally, chylomicron remnants are cleared from the plasma by the liver, due to interaction of ApoE with low density lipoprotein receptor (LDLR) and other LDLR related proteins (LRPs) ( Figure 2 ) [ 34 ].…”