Biogenesis and Catabolism of Atherogenic Lipoproteins

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SUMMARY/ABSTRACT – OVERALL: More people die of cardiovascular disease (CVD) than any other disease worldwide. Our proposal focuses on the biogenesis and catabolism of atherogenic apoB- containing lipoproteins (apoB-Lps), which are major risk factors for CVD. ApoB-Lps comprise both cholesterol and triglycerides (TGs). Whereas reducing cholesterol is well established to reduce atherosclerosis, it remains to be convincingly determined whether decreasing levels of TGs or the apoB-Lps that carry TGs will decrease CVD. Blocking secretion of apoB-Lps by the liver reduces levels of cholesterol-rich apoB-Lps, such as LDL and its TG-rich precursor VLDL. Unfortunately, such approaches have led to hepatosteatosis. However, human genetic mutation and animal studies demonstrate that reduced liver secretion of TGs does not invariably cause steatosis. By characterizing novel factors and pathways regulating liver apoB-Lp production, intravascular lipolysis, and adipose TG retention and mobilization, we will identify unique targets to reduce circulating apoB- Lps, their infiltration into the artery wall, and atherosclerosis. We will define basic mechanisms in cells and in new rodent models and then correlate our discoveries with human data, emphasizing a translational and transfomative approach. Our overall goals are to: 1) identify new processes and factors regulating circulating TG and FA levels, 2) investigate the lipidation and intracellular transport of apoB in hepatocytes, and 3) study how different apoB-Lps interact with cells and ultimately catalyze atherogenesis. This application comprises three projects (P1–P3) that have integrated work from three established investigators of apoB-Lp metabolism and atherosclerosis. P1 will investigate the role of adipose MTP and FIT2 in regulating adipose lipolysis, circulating lipids, hepatic apoB-Lp production, and atherosclerosis. P2 will study two poorly characterized proteins in the liver, KLHL12 and FIT2, which control hepatic apoB-Lp lipid-loading and secretion, and the composition of atherogenic apoB-Lps. P3 will study how TG-rich apoB-Lps interact with the vascular wall, and specifically determine the role of the N-terminal region of apoB on lipid uptake and transcytosis of apoB-Lps by vascular ECs and their links to atherosclerosis. The PPG has an administrative core and three scientific cores (C1–C3). The Administrative Core will oversee the overall PPG function and finances. To assist P1–P3, C1 will provide biostatistics and bioinformatics support, C2 will perform lipidomics and proteomics on apoB-Lps and tissues and provide human samples, and C3 will perform state-of-the-art atherosclerosis assays. Our studies will generate novel mouse models invaluable to understand the factors that regulate lipid metabolism and atherosclerosis, identify new therapeutic targets, and better define how high circulating levels of atherogenic apoB-Lps and other factors contribute to atherogenesis. Dissecting pathways that regulate the production and atherogenicity of apoB- Lps promises to reveal novel approaches to reduce CVD. This requires the integration of reseach in our three projects, as experiments in each require assistance from the others and core resources.