Apolipoprotein A-I Rotamers, HDL Function and Risk of Cardiovascular Disease in Diabetes

Patients with type 2 diabetes suffer from diabetic dyslipidemia, i.e. elevated levels of plasma triglycerides and low levels of high-density lipoprotein cholesterol (HDL-C), which strongly associates with the risk of cardiovascular disease. Apolipoprotein A-I (APOA1), the major protein in HDL, serves as a structural scaffold to facilitate protein binding and enzyme activation. Two or three APOA1 can orientate in multiple structural rotamers on HDL: LL5/5, LL5/4 and LL5/2. However, little is known about the role of each rotamer in HDL function. We propose to determine the impact of APOA1 rotamers on HDL functions and how diabetes affects the relative abundance of these APOA1 rotamers in humans. This work will provide initial evidence in identifying the structural features responsible for HDL’s cardioprotective functions, which may have important implications for predicting CVD risk in diabetes.