AI Article Synopsis
- Citrin deficiency (CD) is a genetic disorder linked to mutations in the SLC25A13 gene, leading to nutrient metabolism issues like urea cycle failure and fatty liver.
- Researchers studied CD by using induced pluripotent stem cells (CD-iPSCs) from CD patients and found that these cells did not properly produce urea and had higher levels of triglycerides and lipids.
- The study revealed that dysfunctional mitochondrial β-oxidation and altered mitochondrial structures in CD-HLCs contribute to lipid accumulation, and treatment with a specific PPAR-α agonist helped reduce this fat buildup.
Article 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). In this study, we 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-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-α (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. Based on these observations, we conclude that the lipid accumulation in CD-HLCs results from dysfunctional mitochondrial β-oxidation and abnormal mitochondrial structure.
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| http://dx.doi.org/10.1089/scd.2015.0342 | DOI Listing |
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