Discovery of HDL Subspecies and Investigation of Their Associations With Insulin Sensitivity and Early Carotid Atherosclerosis

Abstract

Recent findings from genome-wide association studies and pharmaceutical trials of CETP inhibitors suggest that HDL cholesterol might not fully capture the anti-atherogenic functions of HDL. The protein component of HDL might be more informative in explaining HDL functions because proteins have characteristics that can modify the biological properties of HDL.

In Chapter 1, I examined whether some proteins located in the HDL size or density range by proteomics studies were present in distinct apoA-I HDL subspecies that could be identified and quantified by a novel sandwich ELISA. Known HDL subspecies containing apoA-II, apoC-III and apoE comprised 70%, 6% and 10%, respectively, and found that novel HDL subspecies containing apoC-I, apoJ, alpha-1 antitrypsin, plasminogen, and apoC-II comprised 14%, 7%, 5%, 3% and 1%, respectively, of the total apoA-I in HDL.

HDL that contains apoC-III has been associated with a higher prevalence of obesity and an elevated risk of CHD, opposite to what has been seen for HDL that does not contain apoC-III. To further our knowledge on apoC-III-based HDL subspecies, I investigated their associations with insulin sensitivity measured by oral glucose tolerance test (OGTT) in Chapter 2 and early stages of carotid atherosclerosis measured as carotid intima-media thickness (cIMT) in Chapter 3. Using the novel sandwich ELISA established in Chapter 1, I measured the concentrations of apoA-I in HDL with and without apoC-III in the European multi-center “Relationship between Insulin Sensitivity and Cardiovascular disease” (RISC) study.

ApoA-I in HDL with and without apoC-III demonstrated significantly opposite associations with both 3-year change in insulin sensitivity and cIMT at baseline. ApoA-I with apoC-III was associated with a decrease in insulin sensitivity and higher cIMT, whereas the concentration of apoA-I without apoC-III was associated with an increase in insulin sensitivity and lower cIMT. The results for apoC-III itself in HDL was consistent with apoA-I with apoC-III. Total apoA-I was null in both cases. These findings suggest that the presence of apoC-III on HDL diminishes and impairs otherwise beneficial effects of HDL on glucose regulation and atheroprotection, and support the potential of HDL apoC-III as a promising target for diabetes and atherosclerosis prevention and treatment.