Apolipoprotein B-100–Containing Lipoprotein Metabolism in Subjects With Lipoprotein Lipase Gene Mutations

Abstract

Objective We investigated the impact of lipoprotein lipase (LPL) gene mutations on apolipoprotein (apo) B-100 metabolism. Methods and Results We studied 3 subjects with familial LPL deficiency (FLD), 14 subjects heterozygous for the LPL gene mutations, Gly188Glu, Trp64Stop and Ile194Thr, and 10 control subjects. Very-low density lipoprotein (VLDL), intermediate-density lipoprotein (IDL) and low-density lipoprotein (LDL)-apoB-100 kinetics were determined in the fed state using stable isotope methods and compartmental modeling. Compared with controls, FLD had markedly elevated plasma triglycerides and lower VLDL-apoB-100 fractional catabolic rate (FCR), IDL-apoB-100 FCR, VLDL-to-IDL conversion and VLDL-apoB-100 production rate (PR) (p<0.01). Compared with controls, Gly188Glu had higher plasma triglyceride, VLDL- and IDL-apoB-100 concentrations, and lower VLDL- and IDL-apoB-100 FCR (p<0.05). Plasma triglycerides were not different but IDL-apoB-100 concentration and PR, and VLDL-to-IDL conversion were lower in Trp64Stop compared with controls (p<0.05). No differences between controls and Ile194Thr were observed. Conclusions Our results confirm that hypertriglyceridemia is a key feature of familial LPL deficiency. This is due to impaired VLDL- and IDL-apoB-100 catabolism and VLDL-to-IDL conversion. Single allele mutations of the LPL gene result in modest to elevated plasma triglycerides. The changes in plasma triglycerides and apoB-100 kinetics are attributable to the effects of the LPL genotype.

Post-Heparin LPL Activity Measurement Using VLDL As a Substrate: A New Robust Method for Routine Assessment of Plasma Triglyceride Lipolysis Defects

“…According with our findings, Surendram [8] recently described 2 LPL and 1 GPIHBP1 new heterozygous missense mutations with normal LPL activity. All these findings are consistent with the knowledge that under dietetic conditions, patients with heterozygous LPL mutations have normal or mildly increased TG levels due to sufficient residual LPL activity [38]. Interestingly, LPL activity levels in our patients with APOA5 mutations were highly heterogeneous.…”

Association of common gene-smoking interactions with elevated plasma apolipoprotein B concentration

“…The current results are in accordance with previous studies suggesting that smoking may alter the expression of genes influencing HDL metabolism or TG and LDL particle size [42]. Each of the genetic modulators included in this study, namely PPARα-L162V, heterozygous loss-of function LPL mutation, apo e4 allele or apo E2/2 genotype, is associated with a plasma apoB concentration increase, by acting on specific apoB-containing lipoproteins [7][8][9]. Various mechanisms could explain this interaction that could be partly due, for instance, to the unfavorable interaction between apo E4 and smoking, as well as to a reduced LPL activity previously observed among smokers [43][44][45].…”

“…ApoE gene polymorphisms, the peroxisome proliferator-activated receptor (PPAR)α-L162V mutation, as well as loss-of-function (LoF) lipoprotein lipase (LPL) gene mutations, are examples of common variants modulating apoB-containing lipoprotein metabolism. PPARα-L162V mutation and several LoF LPL gene variants have been associated with higher apoB levels [7,8]. The differential contribution of common apoE polymorphisms (APOE2, 3 and 4) to apoBcontaining lipoprotein metabolism is also well documented.…”

Kinetic and Related Determinants of Plasma Triglyceride Concentration in Abdominal Obesity

“…10 Because LPL is rate limiting for plasma triglyceride clearance and tissue uptake of fatty acids, the activity of LPL is carefully controlled via multiple mechanisms at both the transcriptional and post-translational level. 7,11 Whereas LPL is predominantly a triglyceride lipase, hepatic lipase is both a phospholipase and a triglyceride lipase which plays an important role in the conversion of VLDL to low-density lipoprotein.…”