Cellular modeling of citrin deficiency using human induced pluripotent stem cells

Abstract

Citrin deficiency (CD) is a recessive genetic disorder caused by mutations in the citrin gene SLC25A13. CD causes various symptoms related to nutrient metabolism such as urea cycle failure, abnormal amino acid levels, and fatty liver. To understand the pathophysiology of CD, the molecular phenotypes were investigated using induced pluripotent stem cells derived from fibroblasts of CD patient (CD-iPSCs). Here I demonstrate that aberrant mitochondrial β-oxidation may lead to fatty liver in CD patients. CD-iPSCs normally differentiated into hepatocytes, similar to wild-type iPSCs (WT-iPSCs). However, hepatocytes derived from CD-iPSCs (CD-hepatocytes) did not exhibit ureogenesis. Cellular triglyceride and lipid granule levels were significantly increased in CD-hepatocytes compared with WT-hepatocytes. PPAR-α and its target genes which are involved in mitochondrial β-oxidation were downregulated in CD-hepatocytes, and treatment with a PPAR-α agonist partially reduced the lipid accumulation in CD-hepatocytes. In addition, the mitochondria in CD-hepatocytes exhibited abnormal morphologies. Based on these observations, I conclude that the lipid accumulation in CD-hepatocytes results from dysfunctional mitochondrial β-oxidation and abnormal mitochondrial structure.