2 Although environmental factors contribute to plasma LDL-C concentration, genome-wide association studies (GWAS) performed on >100,000 patients have identified genetic variants at 95 loci that are closely associated with cholesterol and lipid levels linked to CAD.3 Some of these genetic variants are associated with genes encoding proteins with known roles in regulating cholesterol metabolism, including low-density lipoprotein receptor (LDLR), low-density lipoprotein receptor–associated selleck kinase inhibitor protein 1 (LDLRAP1), and scavenger receptor class B, member 1 (SCARB1). In addition

to identifying genes with known roles in controlling cholesterol flux, GWAS uncovered many novel loci whose contribution to CAD is not understood. Historically, linking genetic findings to biological mechanisms has proven to be a challenge. In some cases, the mouse has provided a suitable system to relate genetic variation

to the pathophysiology of disease; however, the usefulness FG4592 of the mouse is tempered by differences from humans in terms of physiology, metabolism, and genetics, and this is exacerbated when complex traits are being analyzed. Cell culture models can also be useful; however, cholesterol metabolism is predominantly controlled by hepatocytes, and obtaining primary liver cells from patients would require a liver biopsy. Moreover, when primary hepatocytes are cultured, the cells quickly dedifferentiate and lose key liver functions, rendering them unsuitable for detailed metabolic studies. Recently, it has been shown that human induced pluripotent stem cells (hiPSCs) can differentiate into cells

that are functionally similar to hepatocytes.4-6 Because hiPSCs can be reprogrammed from easily accessible somatic cell types, such as skin fibroblasts, this raises the possibility of using hiPSCs from GWAS patients as a source of hepatocytes to study the role of specific allelic variants in regulating cholesterol metabolism. In addition, the availability of hepatocytes derived from patients with inborn errors in hepatic metabolism could provide a platform for drug discovery. Although the use of hiPSC-derived hepatocytes to recapitulate click here metabolic liver disease in culture is conceptually appealing, direct evidence demonstrating the validity of such an approach is scarce.7 Importantly, although iPSC-derived hepatocyte-like cells can be generated with high efficiency, the resulting cells fail to express the complete repertoire of proteins found in adult primary hepatocytes and do not fully silence expression of fetal hepatocyte messenger RNAs (mRNAs) such as AFP.4 These observations have raised questions over the credibility of using iPSCs to study hepatic dysfunction.