👤 Dror Harats

Apolipoprotein A-V plays an important role in reducing plasma triglyceride levels. We hypothesized that expression of apoA-V would inhibit atherogenesis in apoE(-/-) mice fed chow diet which is a known model of hypercholesterolemia. Our aim was to study this protective effect and to explore possible mechanisms. ApoA-V(+/+)ApoE(-/-) mice expressing human apolipoprotein A-V (hapoA-V) were generated and compared to apoE(-/-) mice. Atherosclerotic aortic sinus lesion area was 70% smaller in hapoA-V(+/+)apoE(-/-). This was accompanied by a 58% reduction in lesion macrophage content. Furthermore, advanced atherosclerotic lesions in hapoA-V(+/+)apoE(-/-) mice showed features of a more stable plaque, manifested by 59% and 37% higher collagen and α-actin content, respectively. Plasma triglyceride and cholesterol levels in hapoA-V(+/+)apoE(-/-) mice were 47% and 33% lower, respectively. These were associated with a 33% reduction in very low density lipoprotein triglyceride production and 2-fold acceleration in triglyceride-rich lipoprotein clearance in hapoA-V(+/+)apoE(-/-) mice. In addition, hapoA-V(+/+)apoE(-/-) mice showed enhanced insulin sensitivity (25% and 15% improvement in glucose tolerance and insulin responsiveness, respectively). Finally, hapoA-V(+/+)apoE(-/-) displayed a milder systemic inflammatory response compared to apoE(-/-) mice, manifested by 22%, 65% and 15% lower plasma levels of TNFα, IL-1β and IL-6, respectively. We showed that human apolipoprotein A-V is a potent modulator of atherosclerosis in mice through multiple modes of action. These findings may identify apoA-V as a potential therapeutic target for treatment of atherosclerosis. Show less

ApoAV, a newly discovered apoprotein, affects plasma triglyceride level. To determine how this occurs, we studied triglyceride-rich lipoprotein (TRL) metabolism in mice deficient in apoAV. No significant difference in triglyceride production rate was found between apoa5(-/-) mice and controls. The presence or absence of apoAV affected TRL catabolism. After the injection of 14C-palmitate and 3H-cholesterol labeled chylomicrons and (125)I-labeled chylomicron remnants, the disappearance of 14C, 3H, and (125)I was significantly slower in apoa5(-/-) mice relative to controls. This was because of diminished lipolysis of TRL and the reduced rate of uptake of their remnants in apoa5(-/-) mice. Observed elevated cholesterol level was caused by increased high-density lipoprotein (HDL) cholesterol in apoa5(-/-) mice. VLDL from apoa5(-/-) mice were poor substrate for lipoprotein lipase, and did not bind to the low-density lipoprotein (LDL) receptor as well as normal very-low-density lipoprotein (VLDL). LDL receptor levels were slightly elevated in apoa5(-/-) mice consistent with lower remnant uptake rates. These alterations may be the result of the lower apoE-to-apoC ratio found in VLDL isolated from apoa5(-/-) mice. These results support the hypothesis that the absence of apoAV slows lipolysis of TRL and the removal of their remnants by regulating their apoproteins content after secretion. Show less