Apoa5 Q139X truncation predisposes to late-onset hyperchylomicronemia due to lipoprotein lipase impairment

Abstract

While type 1 hyperlipidemia is associated with lipoprotein lipase or apoCII deficiencies, the etiology of type 5 hyperlipidemia remains largely unknown. We explored a new candidate gene, APOA5, for possible causative mutations in a pedigree of late-onset, vertically transmitted hyperchylomicronemia. A heterozygous Q139X mutation in APOA5 was present in both the proband and his affected son but was absent in 200 controls. It was subsequently found in 2 of 140 cases of hyperchylomicronemia. Haplotype analysis suggested the new Q139X as a founder mutation. Family studies showed that 5 of 9 total Q139X carriers had hyperchylomicronemia, 1 patient being homozygote. Severe hypertriglyceridemia in 8 heterozygotes was strictly associated with the presence on the second allele of 1 of 2 previously described triglyceride-raising minor APOA5 haplotypes. Furthermore, ultracentrifugation fraction analysis indicated in carriers an altered association of Apoa5 truncated and WT proteins to lipoproteins, whereas in normal plasma, Apoa5 associated with VLDL and HDL/LDL fractions. APOB100 kinetic studies in 3 severely dyslipidemic patients with Q139X revealed a major impairment of VLDL catabolism. Lipoprotein lipase activity and mass were dramatically reduced in dyslipidemic carriers, leading to severe lipolysis defect. Our observations strongly support in humans a role for APOA5 in lipolysis regulation and in familial hyperchylomicronemia. IntroductionRaised plasma triglyceride (TG) levels are an independent risk factor for coronary artery disease (1) and are influenced by both genetic and environmental factors. Severe hypertriglyceridemia (HTG) is a general condition with a few well-documented genetic contributors, including lipoprotein lipase (LPL), APOC2, and APOE, as well as environmental factors such as diet and/or conditions such as pregnancy and diabetes (2-5). While genetic factors account for a large proportion of the rare type 1 hyperlipidemia, the complex interaction between genetics and environment is only partly understood in the more common type 5 hyperlipidemia.A strong candidate for severe HTG is the recently discovered human apolipoprotein A-V (APOA5) gene based on its profound modulation of plasma TG concentration. In mice, apoa5 overexpression lowered plasma TG concentration (6-8) whereas mice lacking Apoa5 had a 4-fold increase in plasma TG concentration (6). In humans, independent studies have demonstrated that variant haplotypes with either the S19W or the c.A-3G APOA5 polymorphisms are strong determinants of plasma TG

Dietary oxidized linoleic acid lowers triglycerides via APOA5/APOClll dependent mechanisms

“…In mice, adenoviral over expression of murine APOA5 resulted in a decreased production rate of VLDL triglycerides. Most importantly, as determined by APOB kinetic studies using stable isotopes Marcais et al have shown that the VLDL production rate was normal but the fractional catabolic rate of VLDL-APOB was decreased more than 20-fold in patients lacking normal APOA5 [26]. These and previously mentioned evidence demonstrate that APOA5 and ApoClll may have modulated the OxFA induced TG decreases.…”

Apolipoprotein AV does not contribute to hypertriglyceridaemia or triglyceride lowering by dietary fish oil and rosiglitazone in obese Zucker rats

“…In humans with hypertriglyceridaemia or familial combined hyperlipidaemia, polymorphisms in APOA5 show a strong association with plasma triglyceride levels across several ethnic groups [2][3][4]39]. ApoAV deficiency leads to severe hypertriglyceridaemia [40,41]. Recent measurements of plasma apoAV in normolipaemic subjects revealed a weak negative correlation [35,36] or a tendency towards a positive correlation of plasma apoAV and triglycerides (F. G. Schaap et al, unpublished results).…”

Recent advances in physiological lipoprotein metabolism

“…In humans, severe hyperchylomicronemia has been associated with mutations in the apolipoprotein AV (APOAV) gene [64]. ApoAV circulates at very low In the intestinal cell newly synthesized apoB48 follows one of two itineraries.…”