title: Malfunction in Mitochondrial β-Oxidation Contributes to Lipid Accumulation in Hepatocyte-Like Cells Derived from Citrin Deficiency-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). 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.
authors.affiliation: 1 Department of Biological Sciences, KAIST, Daejeon, Republic of Korea.|2 Center for Stem Cell Differentiation , KAIST, Daejeon, Republic of Korea.
authors.forename: Yeji
authors.initials: Y
authors.lastname: Kim
authors.affiliation: 2 Center for Stem Cell Differentiation , KAIST, Daejeon, Republic of Korea.|3 Graduate School of Medical Science and Engineering , KAIST, Daejeon, Republic of Korea.
authors.forename: Jung-Yun
authors.initials: JY
authors.lastname: Choi
authors.affiliation: 4 BioMedical Research Center , KAIST, Daejeon, Republic of Korea.
authors.forename: Sang-Hee
authors.initials: SH
authors.lastname: Lee
authors.affiliation: 5 Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine , Seoul, Republic of Korea.
authors.forename: Beom-Hee
authors.initials: BH
authors.lastname: Lee
authors.affiliation: 5 Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine , Seoul, Republic of Korea.
authors.forename: Han-Wook
authors.initials: HW
authors.lastname: Yoo
authors.affiliation: 1 Department of Biological Sciences, KAIST, Daejeon, Republic of Korea.|2 Center for Stem Cell Differentiation , KAIST, Daejeon, Republic of Korea.
authors.forename: Yong-Mahn
authors.initials: YM
authors.lastname: Han
mesh_terms: D000818:Animals; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D002454:Cell Differentiation; D002478:Cells, Cultured; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000502:physiology*; D050356:Lipid Metabolism; D008819:Mice, Nude; D008930:Mitochondria, Liver / Q000378:metabolism*; D027361:Organic Anion Transporters / Q000378:metabolism*; D010084:Oxidation-Reduction
chemical_list: D002135:Calcium-Binding Proteins; D027361:Organic Anion Transporters; C008822:citrin