Citrin deficiency (CD) is a recessive genetic disorder caused by mutations in SLC25A13 gene which encodes citrin protein. CD patients manifest 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 (iPSCs) derived from dermal fibroblasts of CD patient (CD-iPSCs). Here we demonstrate that aberrant mitochondrial β-oxidation may lead to fatty liver in CD patients. Similar to WT iPSCs, CD-iPSCs normally differentiated into hepatocyte-like cells and represented hepatic characteristics, including expression of hepatocyte-specific genes, albumin secretion, glycogen storage and low density lipoprotein (LDL) uptake ability. However, hepatocyte-like cells (HLCs) derived from CD-iPSCs (CD-HLCs) failed to produce urea from ammonia. Cellular triglyceride and lipid granule levels were significantly increased in CD-HLCs compared with WT-HLCs. This symptom was intensified in the presence of high-glucose. PPAR-α and its target genes which are involved in mitochondrial β-oxidation were downregulated in CD-HLCs, and treatment with a PPAR-α agonist partially reduced the lipid accumulation in CD-HLCs. In addition, the mitochondria in CD-HLCs exhibited abnormal morphologies and decreased mitochondrial protein levels. Based on these observations, we suggest that CD-HLCs partly mimic CD patient symptoms in vitro, and the lipid accumulation in CD-HLCs accounts for dysfunctional mitochondrial β-oxidation and abnormal mitochondrial structures.
11 Jul 2016 - 11 Jul 2016