<International Circulation>: Please summarize the main body of your presentation， "Effect of HDL Subspecies on HDL Function"， and offer us your opinions on HDL mediated RCT (reverse cholesterol transport) in preventing artherosclerisis?
Dr Rye: Cholesterol efflux from macrophages in the artery wall to the periphery is extremely important but there are a lot of other functions of HDL that are also likely to play a role in preventing atherosclerosis. What I have focused on is the ability of HDL to inhibit inflammation and the ability of HDL to inhibit oxidation， I published a paper last year showing that HDL improves pancreatic beta cell function in diabetes.
They are the three things that I focused in my presentation. What I was looking at in each of these was the two main protein components of HDL. They are called ApoA1 and ApoA2 and I looked at ApoA1 relative to ApoA2 in terms of HDL’s ability to inhibit inflammation and the improvement in pancreatic beta cell function–the two key factors involved. In my talk， I discussed the initial in-vitro studies and then our in-vivo study， which was published a few years ago in 2005 in Circulation， where we used a model of acute vascular inflammation rabbit models and showed that ApoA1 inhibits this inflammation extremely well. When inflammation occurs you also get a lot of reactive oxygen species formation and it inhibited that as well. This was a very good demonstration of the anti-oxidant and anti-inflammatory properties of HDL that contains ApoA1. We have done a similar study with ApoA2 and what we found is that ApoA2 also significantly inhibits inflammation and inhibits oxidation but not as effectively as ApoA1. We then went on to look at beta cell function and we did this in a number of ways. We used reconstituted HDL which contained ApoA1 or ApoA2 or just apolipoproteins on their own. Essentially in this situation， ApoA1 and ApoA2 were equally effective. We are trying to figure this out now， but what they do is to increase the release of insulin from beta cells. This is really important if you are looking at people who have insulin resistance. The one thing that concerned me in the initial stages of this study is that you would just deplete the beta cells of insulin and this was worse than doing nothing. What we found however， was that we were not depleting the beta cells of insulin at all， in fact we were increasing insulin synthesis. The insulin content of the cells never changed， it is just that they were able to generate more insulin.
This brings us to a post hoc study (that has just been accepted into Circulation) that we did in a subset of people from the ILLUMINATE study. This was a study run by Pfizer that was terminated in which people were treated with atorvastatin or atorvastatin plus torcetrapib and in the atorvastatin plus torcetrapib arm of this study， the participants， not surprisingly， had substantial increases in HDL levels. We pulled a subset of people from this study who had diabetes and compared them using matched controls (people who didn’t have diabetes) and looked at glycemic control in these people. We found that as HDL levels increased， there was a substantial improvement in glycemic control. There was also an improvement in glycemic control in those people who did not have diabetes but it was not as great as those that did. These studies are really interesting because they tell you something is happening but they don’t actually tell you， for example， that the improvement in glycemic control was caused directly by the increased HDL levels. But when you put the in vitro study we published last year together with this， it actually looks very promising. In addition to reducing cardiovascular risk， if you raise HDL levels， you may also have an effective intervention in people with diabetes.
<International Circulation>: Do you think that these HDL subspecies can be utilized as target therapies for diabetes?
Dr Rye: It is interesting. We only have very scant evidence but it looks very promising. That would just be a bonus because these interventions were developed to reduce cardiovascular risk and were certainly not developed to target diabetes directly. On the other hand， people with diabetes have markedly increased incidence of cardiovascular disease so they would benefit over and above what one would expect from just a reduction in cardiovascular risk.
<International Circulation>: Hypothetically， how do these results translate into humans?
Dr Rye: To get a comprehensive answer， you are going to have to do a combination of studies in humans and animals and cells and so on. I feel that there are the potential added benefits， if looking at CETP inhibition， that there are likely to be other effects of raising HDL that haven’t been considered yet and I think there is quite a lot of mileage in this. What I expect and hope to see in the trials that are now ongoing is that there is a dramatic reduction in morbidity and mortality in the treated arms of those studies. We haven’t got any clues yet， but I think and hope that is what we will see as long as we are not plagued by any of the off-target effects we have seen in the first study with torcetrapib.
HDL亚型抗炎和抗氧化的特性
动脉壁中巨噬细胞内胆固醇外流转化成HDL很重要，但HDL还有许多其他功能在预防动脉粥样硬化的过程中起重要作用。除逆向转运胆固醇之外， HDL还能抑制炎症和氧化反应。2010年我的一项研究表明，HDL可改善糖尿病患者胰岛β细胞功能。
目前，我关注三个问题：HDL中两个主要的蛋白成分即ApoA1和ApoA2，在HDL抑制炎症反应和改善胰岛β细胞功能方面ApoA1和ApoA2的关系。我们复制急性血管炎症的兔模型，结果表明ApoA1能很好地抑制急性炎症反应和许多活性氧成分的生成，这说明HDL的抗氧化和抗炎特性存在于ApoA1中。我们同样也对ApoA2进行相似的研究，结果发现ApoA2也明显抑制炎症和氧化反应，但不如ApoA1有效。之后我们采用了包含ApoA1或ApoA2或仅载脂蛋白的重组HDL继续研究β细胞功能，结果发现，ApoA1和ApoA2同样有效；另外，ApoA1和ApoA2并不耗竭胰岛β细胞，且增加胰岛素的合成，从而增加胰岛素自β细胞的释放。
HDL的水平与血糖控制
我们对ILLUMINATE研究的亚组进行事后分析，结果表明，与接受阿托伐他汀亚组相比，阿托伐他汀联合torcetrapib亚组HDL水平明显增加；与配对的对照组（无糖尿病患者）相比，有糖尿病的亚组患者HDL水平增加的同时，血糖控制明显改善，无糖尿病的患者血糖控制也有改善，只是不如糖尿病患者明显。血糖控制的改善是否直接由HDL水平的增加引起并不明确。2010年我们的体外研究表明，升高HDL水平除能减少心血管风险外，还能有效干预糖尿病患者的血糖。
HDL亚型的靶向治疗
利用HDL的亚型靶向治疗糖尿病，目前只有有限的证据，但很有希望。然而，这仅仅是一种额外获益，因为降脂治疗主要降低心血管风险，并不直接针对糖尿病患者。另一方面，糖尿病患者心血管疾病风险显著增加，所以他们能有心血管风险降低之外的获益。新型非他汀类降胆固醇药物——胆固醇酯转运蛋白（CETP）抑制剂或许会给我们带来意想不到的升高HDL的其他益处。