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Familial hypercholesterolemia (FH) is a common genetic disease and has been studied with the aim of finding a curative measure for decades. FH is caused by mutations in the low-density lipoprotein receptor (LDLR) resulting in defects in LDL-cholesterol (LDL-C)-receptor mediated endocytosis and development of premature cardiovascular disease (CVD). Here I describe the use of a corrected and non-corrected LDLR FH cell model to investigate receptor-mediated endocytosis and statin effects. For these studies, we reprogrammed FH fibroblast cells to induced pluripotent stem cells (iPSC) and confirmed their pluripotency and ability to differentiate to hepatocyte-like cells (HLC). A clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated 9 (Cas9) design was created and used to successfully correct a 3 base pair deletion in the class II LDLR FH iPSC. Western blot and immunocytochemistry analysis showed maturation and proper localization of the LDLR after correction in iPSC and HLC. We used internalization analyses to detect LDL-C receptor mediated endocytosis in non-corrected and corrected HLC. Real time PCR for ER stress markers showed that statin-induced accumulation of an immature LDLR in non-corrected FH cells did not activate the unfolded protein response. Together, this work demonstrates the capacity to utilize the resources of CRISPR, iPSC, and HLC to study misfolded class II LDLR providing a physiologically relevant in vitro model for investigating the differential effects of mutant versus corrected LDLR-mediated metabolism and current treatments like statins.

Cholesterol metabolism and statin effects on an FH class II LDL-receptor mutation.