title: Steatogenesis in adult-onset type II citrullinemia is associated with down-regulation of PPARα.
abstract: SLC25A13 (citrin or aspartate-glutamate carrier 2) is located in the mitochondrial membrane in the liver and its genetic deficiency causes adult-onset type II citrullinemia (CTLN2). CTLN2 is one of the urea cycle disorders characterized by sudden-onset hyperammonemia due to reduced argininosuccinate synthase activity. This disorder is frequently accompanied with hepatosteatosis in the absence of obesity and ethanol consumption. However, the precise mechanism of steatogenesis remains unclear. The expression of genes associated with fatty acid (FA) and triglyceride (TG) metabolism was examined using liver samples obtained from 16 CTLN2 patients and compared with 7 healthy individuals. Although expression of hepatic genes associated with lipogenesis and TG hydrolysis was not changed, the mRNAs encoding enzymes/proteins involved in FA oxidation (carnitine palmitoyl-CoA transferase 1α, medium- and very-long-chain acyl-CoA dehydrogenases, and acyl-CoA oxidase 1), very-low-density lipoprotein secretion (microsomal TG transfer protein), and FA transport (CD36 and FA-binding protein 1), were markedly suppressed in CTLN2 patients. Serum concentrations of ketone bodies were also decreased in these patients, suggesting reduced mitochondrial β-oxidation activity. Consistent with these findings, the expression of peroxisome proliferator-activated receptor α (PPARα), a master regulator of hepatic lipid metabolism, was significantly down-regulated. Hepatic PPARα expression was inversely correlated with severity of steatosis and circulating ammonia and citrulline levels. Additionally, phosphorylation of c-Jun-N-terminal kinase was enhanced in CTLN2 livers, which was likely associated with lower hepatic PPARα. Collectively, down-regulation of PPARα is associated with steatogenesis in CTLN2 patients. These findings provide a novel link between urea cycle disorder, lipid metabolism, and PPARα.
authors.affiliation: Department of Medicine (Gastroenterology), Shinshu University School of Medicine, Japan.
authors.forename: Michiharu
authors.initials: M
authors.lastname: Komatsu
authors.affiliation: Department of Medicine (Gastroenterology), Shinshu University School of Medicine, Japan; Department of Metabolic Regulation, Shinshu University Graduate School of Medicine, Japan.
authors.forename: Takefumi
authors.initials: T
authors.lastname: Kimura
authors.affiliation: Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, Japan; Department of Biological Sciences for Intractable Neurological Diseases, Institute for Biomedical Sciences, Shinshu University, Japan.
authors.forename: Masahide
authors.initials: M
authors.lastname: Yazaki
authors.affiliation: Department of Medicine (Gastroenterology), Shinshu University School of Medicine, Japan; Department of Metabolic Regulation, Shinshu University Graduate School of Medicine, Japan. Electronic address: naopi@shinshu-u.ac.jp.
authors.forename: Naoki
authors.initials: N
authors.lastname: Tanaka
authors.affiliation: Department of Metabolic Regulation, Shinshu University Graduate School of Medicine, Japan.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Metabolic Regulation, Shinshu University Graduate School of Medicine, Japan.
authors.forename: Takero
authors.initials: T
authors.lastname: Nakajima
authors.affiliation: Digestive Disease Center, Showa Inan General Hospital, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Horiuchi
authors.affiliation: Department of Toxicology, School of Public Health, Tianjin Medical University, China.
authors.forename: Zhong-Ze
authors.initials: ZZ
authors.lastname: Fang
authors.affiliation: Department of Medicine (Gastroenterology), Shinshu University School of Medicine, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Joshita
authors.affiliation: Department of Medicine (Gastroenterology), Shinshu University School of Medicine, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Matsumoto
authors.affiliation: Department of Medicine (Gastroenterology), Shinshu University School of Medicine, Japan.
authors.forename: Takeji
authors.initials: T
authors.lastname: Umemura
authors.affiliation: Department of Medicine (Gastroenterology), Shinshu University School of Medicine, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Tanaka
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, USA.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
authors.affiliation: Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, Japan.
authors.forename: Shu-Ichi
authors.initials: S
authors.lastname: Ikeda
authors.affiliation: Department of Metabolic Regulation, Shinshu University Graduate School of Medicine, Japan.
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Aoyama
mesh_terms: D000328:Adult; D020159:Citrullinemia / Q000150:complications / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015536:Down-Regulation; D005227:Fatty Acids / Q000235:genetics / Q000378:metabolism; D005234:Fatty Liver / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D007657:Ketone Bodies / Q000235:genetics / Q000378:metabolism; D050356:Lipid Metabolism; D008297:Male; D008875:Middle Aged; D008930:Mitochondria, Liver / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D033681:Mitochondrial Membrane Transport Proteins; D047493:PPAR alpha / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D014280:Triglycerides / Q000235:genetics / Q000378:metabolism
chemical_list: D005227:Fatty Acids; D007657:Ketone Bodies; D033681:Mitochondrial Membrane Transport Proteins; D047493:PPAR alpha; D012333:RNA, Messenger; C119629:SLC25A13 protein, human; D014280:Triglycerides; D048031:JNK Mitogen-Activated Protein Kinases
keywords: JNK; Mitochondrial β-oxidation; NAFLD; PPARα; SLC25A13; Urea cycle disorder