Plasma concentrations of lipids (LDL-C, HDL-C and triglycerides) are important risk factors for atherosclerotic cardiovascular disease and have proven fertile territory for genome-wide association studies (GWAS). The Global Lipids Genetics Consortium, a consortium of lipid GWAS totaling approximately 100,000 subjects, has identified a total of 95 loci that are genome-wide significantly associated with at least one plasma lipid trait. While this list includes most of the genes that are known causes of Mendelian lipid disorders, the majority are not previously associated with lipoprotein metabolism. It is key to determine how these genetic loci affect phenotypes in human tissue types relevant to lipid metabolism, especially the liver. This will lead to a greater understanding of the physiological regulation of lipoprotein metabolism and identify novel therapeutic targets for reducing LDL-C and TG and raising HDL-C. There is a need to establish infinitely renewable sources of functional hepatocytes from patients with defined genotype in order to study the cellular mechanisms by which genotype influences hepatocyte lipid biology and plasma lipid traits. We have developed the ability to use adipose stem cells (ASCs) to serve as the basis for obtaining reprogrammed induced pluripotent stem (iPS) cells and have a core dedicated to both ASC isolation and to scaling up iPS generation. Through collaboration between Penn and Medical College of Wisconsin we have established protocols for the differentiation of human iPS cells into hepatocytes. Our consortium comprises investigators expert in iPS generation, hepatocyte generation, and hepatocyte lipid metabolism. We will develop a library of iPS cell lines and iPS-derived hepatocytes from ~300 hundred subjects with defined genotypes and will use them to (1) develop highly efficient and reliable protocols to obtain iPS cell lines from ASCs, followed by differentiation into functional hepatocytes;(2) scale up these protocols to enable high- throughput generation of iPS cell lines and hepatocytes;and (3) perform metabolic profiling from these hepatocytes. These studies should provide novel insights into the molecular mechanisms by which some of the most compelling GWAS loci for plasma lipid traits influence lipoprotein metabolism.
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