Effect of apolipoprotein A-V on plasma triglyceride, lipoprotein size, and composition in genetically engineered mice

Abstract

Transgenic (Tg) mice that overexpress the human apolipoprotein A-V gene (APOA5) yet lack an endogenous mouse apoa5 gene (APOA5 Tg mice) were generated. Subsequently, the effect of human apoA-V expression on plasma triglyceride (TG) concentration and lipoprotein and apolipoprotein distribution was determined and compared with that in mice deficient in apoA-V (apoa5 2/2 mice). NMR analysis of plasma lipoproteins revealed that APOA5 Tg mice had a very low VLDL concentration (26.4 6 7.7 nmol/dl), whereas VLDL in apoa5 2/2 mice was 18-fold higher (467 6 152 nmol/dl). SDS-PAGE analysis of the d , 1.063 g/ml plasma fraction revealed that the apoB-100/ apoB-48 ratio was 14-fold higher in APOA5 Tg versus apoa5 2/2 mice and that the apoE/total apoB ratio was 7-fold greater in APOA5 Tg versus apoa5 2/2 mice. It is anticipated that a reduction in apoB-100/apoB-48 ratio as well as that for apoE/apoB would impair the uptake of VLDL and remnants in apoa5 2/2 mice, thereby contributing to increased plasma TG levels. The concentration of apoA-V in APOA5 Tg mice was 12.5 6 2.9 mg/ml, which is ?50-to 100-fold higher than that reported for normolipidemic humans. ApoA-V was predominantly associated with HDL but was rapidly and efficiently redistributed to apoA-V-deficient VLDL upon incubation. Consistent with findings reported for human subjects, apoA-V concentration was positively correlated with TG levels in normolipidemic APOA5 Tg mice. It is conceivable that, in a situation in which apoA-V is chronically overexpressed, complex interactions among factors regulating TG homeostasis may result in a positive correlation of apoA-V with TG concentrations. Plasma triglyceride (TG) is an independent risk factor in cardiovascular disease and is implicated in the development of the metabolic syndrome, characterized by insulin resistance, hypertension, obesity, and a proinflammatory condition. Apolipoprotein A-V (apoA-V) has been identified as a regulator of plasma TG concentrations in humans and mice. Mice overexpressing apoA-V had significantly reduced (70%) plasma TG concentrations, whereas apoA-V-deficient (apoa5 2/2 ) mice had an ?4-fold increase in plasma TG compared with control littermates (1). Adenovirus-mediated overexpression of human apoA-V in mice was shown to diminish plasma VLDL-TG levels in a dose-dependent manner (2). Genetic studies in human populations have identified polymorphisms in APOA5 that correlate with increased plasma TG and risk for cardiovascular disease (3-6). Truncation mutations in APOA5 have been identified that are associated with severe familial hypertriglyceridemia and chylomicronemia (7,8), suggesting that apoA-V modulates plasma TG concentrations.The APOA5 gene is located in the APOA1/C3/A4 gene cluster and is expressed only in the liver. Moreover, van der Vliet et al. (9) observed that apoA-V mRNA expression increased by 3-fold during early liver regeneration in the rat. In humans, the circulating concentration of apoA-V is exceedingly low compared with that for other apolipoproteins. Various...

Molecular cloning, expression and polymorphism of the porcine apolipoprotein A5 gene in a Jinhua × Pietrain F2 reference population

“…APOA5 can enhance lipoprotein lipase (LPL) activity to accelerate the rate of LPL-mediated triglyceride hydrolysis to regulate triglyceride metabolism (Schaap et al, 2004;Rensen et al, 2005). It had been found that several haplotypes of APOA5 gene were related with the significant changes in triglyceride level (Grallert et al, 2007;Nelbach et al, 2008). In rat, the percentage of body fat was significantly correlated with serum triglyceride (Paik and Yearick, 1978), and in the young females and male pigs, the triglyceride level was positively correlated with backfat thickness (Mersmann and MacNeil, 1985).…”

Multiple genetic variants along candidate pathways influence plasma high-density lipoprotein cholesterol concentrations

“…c Statistical analysis and calculation were only conducted in women. (32). There are numerous reports on the association of genetic variants of APOA5 with low HDL-C levels, such as rs662799, rs651821, and rs2075291 in Japanese populations (33) and Chinese populations (34).…”

Biogenesis of apolipoprotein A-V and its impact on VLDL triglyceride secretion

“…In humans, several loss-of-function and null apoA-V alleles are associated with both reduced plasma apoA-V levels and elevated plasma TG ( 12, 13 ), yet other studies have found both positive and negative associations between plasma apoA-V and TG concentrations ( 7,14,15 ). Moreover, recent studies in mice have found a positive correlation between plasma apoA-V and TG concentrations ( 16,17 ).…”

“…In humans, several loss-of-function and null apoA-V alleles are associated with both reduced plasma apoA-V levels and elevated plasma TG ( 12, 13 ), yet other studies have found both positive and negative associations between plasma apoA-V and TG concentrations ( 7,14,15 ). Moreover, recent studies in mice have found a positive correlation between plasma apoA-V and TG concentrations ( 16,17 ).Despite its apparent impact on intravascular TG-rich lipoprotein lipolysis and clearance, a peculiar characteristic of apoA-V is that its plasma concentration is in the range of 100-200 µg/l, which is ‫ف‬ 10,000-fold lower than apoA-I and ‫ف‬ 1,000-fold lower than apoA-IV and corresponds to ‫ف‬ 1 molecule of apoA-V for every 1,000 VLDL particles ( 18,19 ). This presents a conundrum as to how an apolipoprotein circulating at such low levels could exert such a potent effect on plasma TG metabolism and concentration.…”