Plasma apolipoprotein AV levels in mice are positively associated with plasma triglyceride levels

Abstract

Apolipoprotein AV (apoAV) overexpression causes a decrease in plasma triglyceride (TG) levels, while deficiency of apoAV causes hypertriglyceridemia in both men and mice. However, contrary to what would be expected, plasma apoAV and TG levels in humans are positively correlated. To address this apparent paradox, we determined plasma apoAV levels in various mouse models with median TG levels ranging from 30 mg/dl in wild-type mice to 2089 mg/dl in glycosylphosphatidylinositol-anchored HDL binding protein 1-deficient mice. The data show that apoAV and TG levels are positively correlated in mice (r 5 10.798, P , 0.001). In addition, we show that LPL gene transfer caused a simultaneous decrease in TG and apoAV in LPL-deficient mice. The combined data suggest that apoAV levels follow TG levels due to an intimate link between the apoAV molecule and TG-rich lipoproteins, comprising both secretion and removal of these lipoproteins. Taken together, the data suggest that higher plasma apoAV levels reflect an increased demand for plasma TG hydrolysis under normal physiological conditions.-Vaessen, S. Since its discovery in 2001, apolipoprotein AV (apoAV) has been postulated as a key regulator of plasma triglyceride (TG) levels (1). Relevance for TG homeostasis was initially demonstrated using genetically engineered mice: Overexpression of human apoAV decreased plasma TG by 64%, while apoa5-deficient mice had 4-fold increased plasma TG levels (1). In humans, it was furthermore shown that variation at the APOA5 gene locus was associated with TG levels (2-4), while complete apoAV deficiency was associated with severe hypertriglyceridemia (5, 6). Combined, these data suggested that plasma levels of apoAV are in general inversely correlated with TG levels. However, we and others subsequently showed that plasma apoAV and TG levels are, unexpectedly, positively correlated in patients with type 2 diabetes and in the general population (7-11). Considering the suggested negative correlation between plasma apoAV and TG in mice, based on the overexpression models, these subsequent observations in humans have led several investigators to suggest an inherent difference between humans and mice (10-12). This despite the fact that the phenotypic presentation of complete apoAV deficiency in mice and humans is similar (1, 5). Moreover, in mice with endotoxemia (13) or in rats fed PUFAs (14), semiquantification of apoAV levels by immunoblotting also suggested a positive correlation with TG levels. In addition, Nelbach et al. (15) recently showed a positive correlation between plasma apoAV and TG concentrations in mice overexpressing human apoAV. In this study, we further addressed this hypothesis by determining the relationship between plasma apoAV and TG levels in wild-type mice and various genetically engineered mouse models that are characterized by a wide range of elevated levels of plasma triglycerides. METHODS Mouse modelsTo determine the association between plasma apoAV and TG levels in mice, we collected plasma samples from ...

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 ).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.…”

“…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 ).…”

Synthesis of recombinant high density lipoprotein with apolipoprotein A-I and apolipoprotein A-V

“…In vivo data suggest an apoA-V-mediated faster removal of TG-rich lipoproteins rather than an increased production mechanism (Kluger et al, 2008). Vaessen and coworkers believe that higher plasma apoA-V levels reflect an increased demand for plasma TG hydrolysis under physiological conditions in mice (Vaessen et al, 2009 the presence of a high concentration of recombinant apoA-V (600 mg/ml). It was thought that apoA-V at high concentrations might produce non-specific hydrophobic interactions increasing hydrolysis or stabilizing functional LPL in vitro (Merkel et al, 2005).…”

“…Mice overexpressing human apoA-V showed a decrease in plasma TG levels to one-third of those in control littermates; whereas, apoA-V knockout (apoA-V -/-) mice had approximately four times higher plasma TG levels than that of control littermates (Pennacchio et al, 2001). In wild-type and Gpihbp1 -/-mice with median TG levels, the apoA-V and TG levels are reported to be positively correlated suggesting that higher plasma apoA-V levels reflect an increased demand for plasma TG hydrolysis under physiological conditions (Vaessen et al, 2009). Although the relationship between apoA-V and plasma TG has been well characterized, little is known about its effects on lipoprotein metabolism and other functions aside from modulating TG homeostasis.…”

Apolipoprotein A-V dependent modulation of plasma triacylglycerol: A puzzlement

“…Severely elevated plasma TG and reduced clearance of apoA-V in GPIHBP1 deficiency are not specific to this metabolic aberration. Vaessen et al [21] examined plasma TG and apoA-V levels in lpl −/− mice and noted a parallel elevation of TG and apoA-V. LPL gene transfer into LPL deficient mice resulted in a simultaneous decrease in TG and apoA-V. Thus, hydrolysis of TG-rich lipoproteins is necessary for normal clearance of apoA-V transported on CM and VLDL.…”