LIPA gene mutations affect the composition of lipoproteins: Enrichment in ACAT-derived cholesteryl esters

Abstract

Background and aimsCholesteryl ester storage disease (CESD) due to LIPA gene mutations is characterized by hepatic steatosis, hypercholesterolemia and hypoalphalipoproteinemia, exposing affected patients to an increased cardiovascular risk. Further insights into the impact of LIPA gene mutations on lipid/lipoprotein metabolism are limited. Aim of the study was to investigate the effect of carrying one or two mutant LIPA alleles on lipoprotein composition and function. MethodsLipoproteins were isolated from 6 adult CESD patients, 5 relatives carrying one mutant LIPA allele (carriers) and 12 sex/age matched controls. Lipid profile, lipoprotein mass composition and the fatty acid distribution of cholesteryl esters (CEs) were assessed. HDL function was evaluated as the ability to promote nitric oxide release by endothelial cells. ResultsDespite the lipid-lowering therapy, total cholesterol, LDL-cholesterol and triglycerides were increased in CESD patients compared to controls, while HDL-cholesterol was reduced.Carriers also displayed elevated total and LDL-cholesterol. Very low and intermediate density lipoproteins from CESD patients and carriers were enriched in CEs compared to the control ones, with a concomitant reduction of triglycerides. Fatty acid composition of CEs in serum and lipoproteins showed a depletion of linoleate content in CESD patients, due to the reduced LCAT activity. In CESD HDL, fatty acid distribution of CEs was shifted towards saturated ones, if compared to control HDL. The changes in HDL composition did not affect HDL ability to promote nitric oxide release by endothelial cells. ConclusionsLIPA gene mutations significantly affected plasma levels and lipid composition of lipoproteins, likely contributing to the increased cardiovascular risk of affected patients.

Within- and between-Breed Selection Signatures in the Original and Improved Valachian Sheep

“…Our top signal directly overlaps with the genes LIPA , IFIT2 , IFIT3 , IFIT5 , SLC16A12 and three pseudogenes. The LIPA gene was found to be involved in the lipid mechanism and composition of lipoproteins [ 20 ], response to wounds and inflammations [ 21 ], but also in molecular genetic mechanisms affecting fecundity in sheep [ 22 ]. The family of IFIT genes was shown to have antiviral functions [ 23 ].…”

Epigenetic and transcriptomic alterations in offspring born to women with type 1 diabetes (the EPICOM study)

“…Applying this method provided us with six genes where changes in DNA methylation between offspring exposed to maternal T1DM and controls correlated with relevant changes in gene expression (Table 3). PXN, which is localized at chromosome 12, has been linked to progression of T1DM and LIPA at chromosome 10 to the composition of lipoproteins [42,43]. Mutations in TPM1 at chromosome 15 is associated with both the development of the metabolic syndrome and cardiac hypertrophy [44,45].…”

Epigenetic And Transcriptomic Alterations in Offspring Born To Women With Type 1 Diabetes (The EPICOM Study)

“…Applying this method, provided us with six genes where changes in DNA methylation between offspring exposed to maternal T1DM and controls correlated with relevant changes in gene expression (Table 3). PXN, which is localized at chromosome 12 has been linked to progression of T1DM and LIPA at chromosome 10 to the composition of lipoproteins 24,25 . Mutations in TPM1 at chromosome 15 is associated with both the development of the metabolic syndrome and cardiac hypertrophy 26,27 .…”