Abstract
BackgroundHaptoglobin is a plasma protein that scavenges haemoglobin during haemolysis. Phospholipid Transfer Protein (PLTP) transfers lipids from Low Density Lipoproteins (LDL) to High Density Lipoproteins (HDL). PLTP is involved in the pathogenesis of atherosclerosis which causes coronary artery disease, the leading cause of death in North America. It has been shown that Apolipoprotein-A1 (Apo-A1) binds and regulates PLTP activity. Haptoglobin can also bind to Apo-A1, affecting the ability of Apo-A1 to induce enzymatic activities. Thus we hypothesize that haptoglobin inhibits PLTP activity. This work tested the effect of Haptoglobin and Apo-A1 addition on PLTP activity in human plasma samples. The results will contribute to our understanding of the role of haptoglobin on modulating reverse cholesterol transport.ResultsWe analyzed the PLTP activity and Apo-A1 and Haptoglobin content in six hyperlipidemic and six normolipidemic plasmas. We found that Apo-A1 levels are proportional to PLTP activity in hyperlipidemic (R2 = 0.66, p < 0.05) but not in normolipidemic human plasma. Haptoglobin levels and PLTP activity are inversely proportional in hyperlipidemic plasmas (R2 = 0.57, p > 0.05). When the PLTP activity was graphed versus the Hp/Apo-A1 ratio in hyperlipidemic plasma there was a significant correlation (R2 = 0.69, p < 0.05) suggesting that PLTP activity is affected by the combined effect of Apo-A1 and haptoglobin. When haptoglobin was added to individual hyperlipidemic plasma samples there was a dose dependent decrease in PLTP activity. In these samples we also found a negative correlation (-0.59, p < 0.05) between PLTP activity and Hp/Apo-A1. When we added an amount of haptoglobin equivalent to 100% of the basal levels, we found a 64 ± 23% decrease (p < 0.05) in PLTP activity compared to basal PLTP activity. We tested the hypothesis that additional Apo-A1 would induce PLTP activity. Interestingly we found a dose dependent decrease in PLTP activity upon Apo-A1 addition. When both Apo-A1 and Hpt were added to the plasma samples there was no further reduction in PLTP activity suggesting that they act through a common pathway.ConclusionThese findings suggest an inhibitory effect of Haptoglobin over PLTP activity in hyperlipidemic plasma that may contribute to the regulation of reverse cholesterol transport.
Highlights
Haptoglobin is a plasma protein that scavenges haemoglobin during haemolysis
When we graphed the Phospholipid Transfer Protein (PLTP) activity vs. the haptoglobin levels we found a trend of a correlation
It has been proposed that an enhanced oxidative modification of serum lipoproteins (LDL and High Density Lipoproteins (HDL)) in individuals with the Hp2 genotype is an important determinant of accelerated atherosclerosis in these individuals [22]
Summary
Haptoglobin is a plasma protein that scavenges haemoglobin during haemolysis. Phospholipid Transfer Protein (PLTP) transfers lipids from Low Density Lipoproteins (LDL) to High Density Lipoproteins (HDL). Haptoglobin has been shown to play an antioxidant/anti-inflammatory role, to contribute to neutrophil activation [6], to maintain reverse cholesterol transport [7] and to modulate the inhibition of cyclooxygenase and lipooxygenase [8], amongst other functions. LCAT transfers an acyl chain from high density lipoprotein (HDL) lecithin to cellular cholesterol This activity is stimulated by the presence of Apo-A1, the main protein constituent of HDL. A peptide designed based on the sequence in Apo-A1 that putatively interacts with Haptoglobin was shown to restore LCAT activity inhibited by Hp demonstrating that the Apo-A1Hp interaction is responsible for the inhibition of LCAT activity Based on this evidence it has been speculated that haptoglobin may play a role in the inhibition of reverse cholesterol transport
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