Complement Factor H Binds to Human Serum Apolipoprotein E and Mediates Complement Regulation on High Density Lipoprotein Particles.

The alternative pathway of complement is an important part of the innate immunity response against foreign particles invading the human body. To avoid damage to host cells, it needs to be efficiently down-regulated by plasma factor H (FH) as exemplified by various diseases caused by mutations in its domains 19-20 (FH19-20) and 5-7 (FH5-7). These regions are also the main interaction sites for microbial pathogens that bind host FH to evade complement attack. We previously showed that inhibition of FH binding by a recombinant FH5-7 construct impairs survival of FH binding pathogens in human blood. In this study we found that upon exposure to full blood, the addition of FH5-7 reduces survival of, surprisingly, also those microbes that are not able to bind FH. This effect was mediated by inhibition of complement regulation and subsequently enhanced neutrophil phagocytosis by FH5-7. We found that although FH5-7 does not reduce complement regulation in the actual fluid phase of plasma, it reduces regulation on HDL particles in plasma. Using affinity chromatography and mass spectrometry we revealed that FH interacts with serum apolipoprotein E (apoE) via FH5-7 domains. Furthermore, binding of FH5-7 to HDL was dependent on the concentration of apoE on the HDL particles. These findings explain why the addition of FH5-7 to plasma leads to excessive complement activation and phagocytosis of microbes in full anticoagulated blood. In conclusion, our data show how FH interacts with apoE molecules via domains 5-7 and regulates alternative pathway activation on plasma HDL particles.

Cholesterol efflux and reverse cholesterol transport.

Both alterations of lipid/lipoprotein metabolism and inflammatory events contribute to the formation of the atherosclerotic plaque, characterized by the accumulation of abnormal amounts of cholesterol and macrophages in the artery wall. Reverse cholesterol transport (RCT) may counteract the pathogenic events leading to the formation and development of atheroma, by promoting the high-density lipoprotein (HDL)-mediated removal of cholesterol from the artery wall. Recent in vivo studies established the inverse relationship between RCT efficiency and atherosclerotic cardiovascular diseases (CVD), thus suggesting that the promotion of this process may represent a novel strategy to reduce atherosclerotic plaque burden and subsequent cardiovascular events. HDL plays a primary role in all stages of RCT: (1) cholesterol efflux, where these lipoproteins remove excess cholesterol from cells; (2) lipoprotein remodeling, where HDL undergo structural modifications with possible impact on their function; and (3) hepatic lipid uptake, where HDL releases cholesterol to the liver, for the final excretion into bile and feces. Although the inverse association between HDL plasma levels and CVD risk has been postulated for years, recently this concept has been challenged by studies reporting that HDL antiatherogenic functions may be independent of their plasma levels. Therefore, assessment of HDL function, evaluated as the capacity to promote cell cholesterol efflux may offer a better prediction of CVD than HDL levels alone. Consistent with this idea, it has been recently demonstrated that the evaluation of serum cholesterol efflux capacity (CEC) is a predictor of atherosclerosis extent in humans.

Effects of bariatric surgery on HDL structure and functionality: results from a prospective trial.

BACKGROUND: In addition to high-density lipoprotein cholesterol (HDL-C) levels, HDL quality appears also very important for atheroprotection. Obese patients with metabolic syndrome have significantly reduced HDL-C levels and are usually at increased risk for coronary heart disease. Despite that weight loss benefits these patients, its effects on HDL quality and functionality is currently poorly studied. OBJECTIVES: We investigated how rapid weight loss affects HDL structure and its antioxidant potential in patients undergoing a malabsorptive bariatric procedure. METHODS: Fasting plasma samples were collected the day before and 6 months after the bariatric procedure from 20 morbidly obese patients with body mass index >50, then HDL was isolated and analyzed by biochemical techniques. RESULTS: We report a dramatic alteration in the apolipoprotein ratio of HDL that was accompanied by the presence of more mature HDL subspecies and a concomitant increase in the antioxidant potential of HDL. Interestingly, our obese cohort could be distinguished into 2 subgroups. In 35% of patients (n = 7), HDL before surgery had barely detectable apolipoprotein (apo) A-I and apoCIII, and the vast majority of their HDL cholesterol was packed in apoE-containing HDL particles. In the remaining 65% of patients (n = 13), HDL before surgery contained high levels of apoA-I and apoCIII, in addition to apoE. In both subgroups, surgical weight loss resulted in a switch from apoE to apoA-I-containing HDL. CONCLUSIONS: Rapid weight loss exerts a significant improvement in HDL structure and functionality that may contribute to the documented beneficial effect of malabsorptive bariatric procedures on cardiovascular health.