Project 1. Type 2 diabetes, APOC3 and cardiovascular disease

University Of Washington, Seattle WA

Investigators

Linked publications & trials

Abstract

Project 1 Abstract: People with type 1 diabetes (T1D) or type 2 diabetes (T2D) are at greatly increased risk of premature atherosclerotic cardiovascular disease (CVD). The increased risk of CVD in individuals with diabetes is due in part to factors distinct from glucose and LDL-cholesterol and is linked to abnormal metabolism of triglyceride- rich lipoproteins (TRLs) and their remnant lipoprotein particles (RLPs). Elevated plasma levels of apolipoprotein C3 (APOC3), a protein that increases RLP levels, predict incident CVD independently of glycemic control and LDL-cholesterol in individuals with diabetes. Moreover, APOC3 silencing prevents atherosclerosis in mouse models of T1D and T2D. Our preliminary data now show that myeloid cells increase levels of APOC3 already in the prediabetic stage and that APOC3 produced by the liver has marked effects on different lesion cell populations. Project 1 will clarify how myeloid cells govern hepatic secretion of APOC3-rich TRLs and how APOC3-rich TRLs affect lesional cell populations. The overall hypothesis to be addressed is that lipid uptake by cell- bound triggering receptor expressed on myeloid cells 2 (TREM2) in myeloid cells protects hepatocytes from lipid overloading, increased production of APOC3-rich TRLs and atherosclerosis, and that that the adverse effects of APOC3 on lesional cell populations in T2D are mediated by APOC3-enriched TRLs. Project 1 will use mechanistic mouse models of T2D in which TREM2 shedding is modulated to clarify the effects on APOC3 kinetics and TRL production, assembly, and secretion in collaboration with Project 2. Project 1 will use CITE-seq (cellular indexing of transcriptomes and epitopes) on lesions of atherosclerosis to elucidate how hepatic APOC3 silencing alters lesional cell populations. These studies will be complemented by studies in isolated smooth muscle cells and endothelial cells to reveal signaling pathways and cell functions regulated by hepatic APOC3 in collaboration with Projects 2 and 3. Project 1 will also address whether soluble TREM2 predicts incident CVD events in humans with T2D and whether there is a link to APOC3. The overall goal of Project 1 is to provide important insight into APOC3’s mechanisms given that clinical trials to determine if APOC3-silencing therapy reduces CVD risk are on the horizon. Our studies could provide a strong rationale to include subjects with T2D in those trials.