JD induced pluripotent stem cell-derived hepatocytes faithfully recapitulate the pathophysiology of familial hypercholesterolemia

Abstract

Elevated levels of low density lipoprotein cholesterol (LDL-C) in plasma are a major contributor to cardiovascular disease (CVD), which is the leading cause of death worldwide. Genome–wide association studies (GWAS) have identified 95 loci that associate with control of lipid/cholesterol metabolism. Although GWAS results are highly provocative, direct analyses of the contribution of specific allelic variations in regulating LDL-C has been challenging due to the difficulty in accessing appropriate cells from affected patients. The primary cell type responsible for controlling cholesterol and lipid flux is the hepatocyte. Recently we have shown that cells with hepatocyte characteristics can be generated from human induced pluripotent stem cells (iPSC). This finding raises the possibility of using patient–specific iPSC–derived hepatocytes to study the functional contribution of GWAS loci in regulating lipid metabolism. To test the validity of this approach we produced iPSCs from a patient with mutations in the Low density lipoprotein receptor(LDLR) gene that result in familial hypercholesterolemia (FH). Conclusion: We demonstrate that 1) hepatocytes can be efficiently generated from FH iPSCs, 2) in contrast to control cells FH iPSC–derived hepatocytes are deficient in LDL–C uptake, 3) control but not FH iPS cell–derived hepatocytes increase LDL uptake in response to lovastatin, and 4) FH iPSC–derived hepatocytes display a marked elevation in secretion of lipidated ApoB-100. Cumulatively, these findings demonstrate that FH iPSC–derived hepatocytes recapitulate the complex pathophysiology of FH in culture. These results also establish that patient specific iPSC–derived hepatocytes could be used to definitively determine the functional contribution of allelic variation in regulating lipid and cholesterol metabolism and could potentially provide a platform for the identification of novel treatments of CVD.

Reprogramming of COPD lung fibroblasts through formation of induced pluripotent stem cells

“…Several studies have successfully generated iPSCs from a variety of tissues, including lung (36), and from patients with different diseases (3,8,13,24). The present study demonstrates the generation of iPSCs from lung fibroblasts from non-COPD and COPD patients.…”

Modeling Inborn Errors of Hepatic Metabolism Using Induced Pluripotent Stem Cells

“…This list includes several inborn errors of hepatic function. Liver diseases that have been successfully modeled using an iPSC approach include Alpha-1-Antitrypsin Deficiency (ATD) 8, 25–28 , Glycogen Storage Disease 28, 29 , Tyrosinemia Type I 28, 29 , Familial Hypercholesterolemia (FH) 6, 28, 30 , Tangier Disease 31 , Alper’s Disease 32 , Crigler-Najjar Syndrome 29 , and Wilson’s Disease 7 (Table 1). Interestingly, patients with ATD show a variation in the extent of liver disease associated with the mutation.…”

“…Recently, Cayo and colleagues used iPSC-derived hepatocytes to model homozygous FH 30 . Hepatocytes with compound heterozygous mutations in the Low-Density Lipoprotein Receptor (LDLR) revealed a block in LDL uptake, an inability to respond to statin treatment and elevated APOB levels in the medium of the FH cells compared to controls 30 .…”

Induction of Hepatocyte Differentiation in Human Pluripotent Stem Cells

“…As such, successful reduction of LDL-Chol levels may prevent these diseases. Furthermore, hiPS cells derived from patients with familial hypercholesterolemia (FH), which is caused by mutations in the gene encoding the LDL receptor, could provide an effective model for analyzing the mechanism of this condition [29] . Wilson's disease is a congenital metabolic disorder that results in excess copper accumulation in hepatocytes due to a mutation in the ATP7B gene [30] .…”