Structure-Function Analysis of Triglyceride Regulator ApoA-V Using Natural Variants

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PROJECT SUMMARY Hypertriglyceridemia (hyperTG) is common and is causally associated with at least two important medical consequences: recurrent acute pancreatitis when TGs are extremely elevated and atherosclerotic cardiovascular disease (CVD) across a wide range of elevated TGs. Both of these represent unmet medical needs, as current approaches to reducing TGs are often insufficient in reducing extremely elevated TGs, preventing pancreatitis, and/or reducing cardiovascular disease (CVD) risk. These observations emphasize the need for novel therapies to reduce TGs and the clinical sequelae of hyperTG and elevated triglyceride-rich lipoproteins (TRLs). Human genetics studies indicate that TRLs are causally related to risk of pancreatitis and CVD, and have identified a number of potential therapeutic targets. In this project we focus on ApoC-III and ApoA-V, which are genetically validated and reciprocally modulate LPL activity, thereby influencing triglyceride levels and risk of pancreatitis and CVD. This proposal will build upon our work in the current grant cycle and will provide new information regarding ApoA-V and its reciprocal relationship with ApoC-III, as well as enhance the development of ApoA-V based therapeutic strategies to reduce the clinical consequences of elevated TGs and TRLs. We will derive a detailed understanding of the structure-function relationships of ApoA-V and gain greater insight into the mechanisms by which ApoA-V enhances LPL and possibly reduces VLDL secretion. This information will be highly relevant to informing the development of translational therapies that target ApoA-V with the goal of reducing elevated triglycerides and the clinical sequelae of acute pancreatitis and atherosclerotic CVD.