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.

National Institute of Health (NIH)
National Human Genome Research Institute (NHGRI)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZHL1-CSR-N (F1))
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Bookman, Ebony B
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University of Pennsylvania
Internal Medicine/Medicine
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United States
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Pashos, Evanthia E; Park, YoSon; Wang, Xiao et al. (2017) Large, Diverse Population Cohorts of hiPSCs and Derived Hepatocyte-like Cells Reveal Functional Genetic Variation at Blood Lipid-Associated Loci. Cell Stem Cell 20:558-570.e10
Liu, Ying; Conlon, Donna M; Bi, Xin et al. (2017) Lack of MTTP Activity in Pluripotent Stem Cell-Derived Hepatocytes and Cardiomyocytes Abolishes apoB Secretion and Increases Cell Stress. Cell Rep 19:1456-1466
Cayo, Max A; Mallanna, Sunil K; Di Furio, Francesca et al. (2017) A Drug Screen using Human iPSC-Derived Hepatocyte-like Cells Reveals Cardiac Glycosides as a Potential Treatment for Hypercholesterolemia. Cell Stem Cell 20:478-489.e5
Jing, Ran; Duncan, Cameron B; Duncan, Stephen A (2017) A small-molecule screen reveals that HSP90? promotes the conversion of induced pluripotent stem cell-derived endoderm to a hepatic fate and regulates HNF4A turnover. Development 144:1764-1774
Bi, Xin; Pashos, Evanthia E; Cuchel, Marina et al. (2017) ATP-Binding Cassette Transporter A1 Deficiency in Human Induced Pluripotent Stem Cell-Derived Hepatocytes Abrogates HDL Biogenesis and Enhances Triglyceride Secretion. EBioMedicine 18:139-145
Fisher, J B; Pulakanti, K; Rao, S et al. (2017) GATA6 is essential for endoderm formation from human pluripotent stem cells. Biol Open 6:1084-1095
Mallanna, Sunil K; Waas, Matthew; Duncan, Stephen A et al. (2017) N-glycoprotein surfaceome of human induced pluripotent stem cell derived hepatic endoderm. Proteomics 17:
Lin, Jennie; Hu, Yu; Nunez, Sara et al. (2016) Transcriptome-Wide Analysis Reveals Modulation of Human Macrophage Inflammatory Phenotype Through Alternative Splicing. Arterioscler Thromb Vasc Biol 36:1434-47
Zanoni, Paolo; Khetarpal, Sumeet A; Larach, Daniel B et al. (2016) Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease. Science 351:1166-71
Mallanna, Sunil K; Cayo, Max A; Twaroski, Kirk et al. (2016) Mapping the Cell-Surface N-Glycoproteome of Human Hepatocytes Reveals Markers for Selecting a Homogeneous Population of iPSC-Derived Hepatocytes. Stem Cell Reports 7:543-556

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