ApoAV Reduces Plasma Triglycerides by Inhibiting Very Low Density Lipoprotein-Triglyceride (VLDL-TG) Production and Stimulating Lipoprotein Lipase-mediated VLDL-TG Hydrolysis

Abstract

ApoAV has been discovered recently as a novel modifier of triglyceride (TG) metabolism, but the pathways involved are currently unknown. To gain insight into the function of apoAV, adenovirus-mediated gene transfer of murine apoa5 to C57Bl/6 mice was employed. The injection of low doses of Ad-apoa5 (1-5 ؋ 10 8 plaqueforming units/mouse) dose-dependently reduced plasma very low density lipoprotein (VLDL)-TG levels. First, we evaluated whether a reduced hepatic VLDL production contributed to the TG-lowering effect. Ad-apoa5 treatment dose-dependently diminished (29 -37%) the VLDL-TG production rate without affecting VLDL particle production, suggesting that apoAV impairs the lipidation of apoB. Second, Ad-apoa5 treatment dose-dependently reduced (68 -88%) the postprandial hypertriglyceridemia following an intragastric fat load, suggesting that apoAV also stimulates the lipoprotein lipase (LPL)-dependent clearance of TG-rich lipoproteins. Indeed, recombinant apoAV was found to dose-dependently stimulate LPL activity up to 2.3-fold in vitro. Accordingly, intravenously injected VLDL-like TG-rich emulsions were cleared at an accelerated rate concomitant with the increased uptake of emulsion TG-derived fatty acids by skeletal muscle and white adipose tissue in Ad-apoa5-treated mice. From these data, we conclude that apoAV is a potent stimulator of LPL activity. Thus, apoAV lowers plasma TG by both reducing the hepatic VLDL-TG production rate and by enhancing the lipolytic conversion of TG-rich lipoproteins.Hypertriglyceridemia is a risk factor for coronary heart disease independent from the well known risk factors such as elevated LDL 1 and reduced HDL cholesterol levels (1). Recently, a novel apolipoprotein, apoAV, has been identified that strongly influences plasma triglyceride (TG) levels (2, 3). The human APOA5 gene is part of the apolipoprotein gene cluster on chromosome 11q23 that also encompasses APOA1, APOC3, and APOA4. An initial study revealed the association of three single nucleotide polymorphisms within the APOA5 locus with plasma TG levels and VLDL mass in humans (2). Importantly, these metabolic effects were not associated with a genetic marker in the nearby APOC3 gene that is also known to affect plasma TG levels (2). Subsequent studies in diverse ethnic groups uncovered additional single nucleotide polymorphisms including apoAV protein variants and further supported a role for common genetic variations in APOA5 in influencing plasma TG levels (4, 5). Interestingly, in a recent study, minor allele frequencies of 3 of 5 studied single nucleotide polymorphisms were found to be significantly higher in a hypertriglyceridemic population (4).Mouse models confirmed the TG-modulating effects of apoAV observed in humans. Mice expressing a human APOA5 transgene showed a 65% decrease in plasma TG levels compared with control mice (2). Conversely, apoa5 knock-out mice showed a 400% increase in plasma TG concentration (2). Interestingly, the adenovirus-mediated expression of apoAV in mice resulted in a decrease of b...

Benefit of farnesoid X receptor inhibition in obstructive cholestasis

“…In cell culture, CDCA can induce the human apoAV gene promoter via FXR (22), and we demonstrate the in vivo induction of apoAV in WT mice with elevated concentrations of CDCA after BDL. Mice with elevated apoAV have a reduction in serum triglycerides and HDL cholesterol and, conversely, mice lacking apoAV have increased serum triglyceride levels (23,24). Therefore, the marked increases in triglycerides and HDL cholesterol that we found in FXRKO mice after BDL are consistent with reduced apoAV expression and the inability to stimulate VLDL-triglyceride hydrolysis in response to cholestasis.…”

“…Our findings suggest that reduced expression of apoAV is implicated in the hypertriglyceridemia seen in these FXRKO mice. apoAV may act to reduce plasma triglycerides by inhibiting VLDL-triglyceride production and stimulating lipoprotein lipase-mediated VLDL-triglyceride hydrolysis (24). In cell culture, CDCA can induce the human apoAV gene promoter via FXR (22), and we demonstrate the in vivo induction of apoAV in WT mice with elevated concentrations of CDCA after BDL.…”

Lipid-lowering effects of anti-angiopoietin-like 4 antibody recapitulate the lipid phenotype found in angiopoietin-like 4 knockout mice

“…heparin injection (12) or transgenic LPL overexpression (13)(14)(15) is usually associated with decreased HDL cholesterol. Also, adenoviral-mediated overexpression of ApoAV, which may function as an LPL activator, also lowered HDL cholesterol (12). Thus, lower HDL cholesterol may result from the increased LPL activity associated with Angptl4 inhibition.…”

CETP expression reverses the reconstituted HDL-induced increase in VLDL

“…The effect of rHDL on LPL activity was determined essentially as described ( 20 ). First, glycerol tri[ 3 H]oleate-labeled VLDL-like emulsion particles (200 µg of TG, corresponding to a fi nal concentration of 0.5 mg/ml), prepared as described above, were added to the indicated amounts of rHDL (or vehicle containing sucrose or sodium cholate only) and heat-inactivated human serum (20 µl, corresponding to a fi nal concentration of 5% v/v) in a total volume of 75 µl of phosphate-buffered saline.…”