APOC3, HDL Function and Cardiovascular Complications of T1DM

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 DESCRIPTION: Cardiovascular disease (CVD) is the complication of type 1 diabetes mellitus (T1DM) that accounts for the most mortality. The mechanism whereby T1DM exacerbates CVD risk and the underlying atherosclerosis is poorly understood. Preliminary studies suggest that T1DM subjects who are at increased risk of CVD have elevated levels of HDL-associated apolipoprotein C3 (APOC3), and that these changes are replicated in a mouse model of T1DM-accelerated atherosclerosis. Importantly, loss-of-function mutations in the APOC3 gene are known to reduce triglycerides and CVD risk in humans. Triglyceride and HDL metabolism are inextricably linked. However, little is known about the impact of APOC3 on HDL's structure and cardioprotective function. Moreover, recent clinical studies demonstrate that an impaired ability of HDL to mediate sterol efflux from macrophages is the strongest predictor of future CVD events in healthy humans. The proposed studies address the goals of RFA-DK-14-017 by combining prospective studies of CVD risk in T1DM humans and highly mechanistic studies in a mouse model of T1DM. It is hypothesized that HDL-APOC3 associates with the risk of future CVD events in T1DM patients and that the underlying mechanism involves HDL dysfunction (e.g. reduced sterol efflux capacity) mediated by APOC3. The specific aims are to address two key questions: Aim 1. Does the level of APOC3 in HDL predict the risk of future CVD events in patients with T1DM? Case-control studies on HDL metrics of large numbers of T1DM subjects from two prospective studies: the Pittsburgh Epidemiology of Diabetes Complications (EDC) study and the Coronary Artery Calcification in Type 1 Diabetes (CACTI) study will be performed. To determine whether alterations in HDL's protein cargo or HDL particle number generate dysfunctional HDL and increased CVD risk, these studies will compare the abilities of HDL isolated from T1DM CVD cases and controls to promote sterol efflux. Demonstrating that enrichment in APOC3 associates with loss of HDL's sterol efflux capacity would strongly support the proposal that APOC3 contributes to dysfunctional HDL and that such abnormal HDL increases CVD risk in T1DM. Aim 2. Does APOC3 promote HDL dysfunction and atherosclerosis in a mouse model of T1DM? Preliminary data suggest that a mouse model of T1DM-accelerated atherosclerosis mimics the higher APOC3 levels seen in HDL of T1DM humans at risk for CVD, and that APOC3 directly or indirectly impairs HDL function. The proposed studies will evaluate whether APOC3 deficiency or a loss-of-function APOC3 mutant reduces T1DM-accelerated atherosclerosis, and will investigate the underlying mechanisms using Apoc3-/- mice and hepatic expression of APOC3. The regulation of hepatic APOC3 expression by hyperglycemia and insulin deficiency and the effect of diabetes and APOC3 on HDL metrics will also be clarified.