Malfunction in Mitochondrial beta-Oxidation Contributes to Lipid Accumulation in Hepatocyte-Like Cells Derived from Citrin Deficiency-Induced Pluripotent Stem Cells

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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). In this study, we demonstrate that aberrant mitochondrial beta-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-HLCs) did not exhibit ureogenesis. Cellular triglyceride and lipid granule levels were significantly increased in CD-HLCs compared with WT-HLCs. Peroxisome proliferator-activated receptor-alpha (PPAR-alpha) and its target genes which are involved in mitochondrial beta-oxidation were downregulated in CD-HLCs, and treatment with a PPAR-alpha agonist partially reduced the lipid accumulation in CD-HLCs. In addition, the mitochondria in CD-HLCs exhibited abnormal morphologies. Based on these observations, we conclude that the lipid accumulation in CD-HLCs results from dysfunctional mitochondrial beta-oxidation and abnormal mitochondrial structure
Publisher
MARY ANN LIEBERT INC
Issue Date
2016-04
Language
English
Article Type
Article
Keywords

FATTY-ACID-METABOLISM; II CITRULLINEMIA; PPAR-ALPHA; EXPRESSION; GENE; ACTIVATION; TOXICITY; PROTEIN; DEFECT

Citation

STEM CELLS AND DEVELOPMENT, v.25, no.8, pp.636 - 647

ISSN
1547-3287
DOI
10.1089/scd.2015.0342
URI
http://hdl.handle.net/10203/209013
Appears in Collection
BS-Journal Papers(저널논문)
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