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Steatogenesis in adult-onset type II citrullinemia is associated with down-regulation of PPARα.
- Source :
-
Biochimica et biophysica acta [Biochim Biophys Acta] 2015 Mar; Vol. 1852 (3), pp. 473-81. Date of Electronic Publication: 2014 Dec 20. - Publication Year :
- 2015
-
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.<br /> (Copyright © 2014 Elsevier B.V. All rights reserved.)
- Subjects :
- Adult
Citrullinemia complications
Citrullinemia genetics
Citrullinemia pathology
Fatty Acids genetics
Fatty Acids metabolism
Fatty Liver etiology
Fatty Liver genetics
Fatty Liver pathology
Female
Humans
JNK Mitogen-Activated Protein Kinases genetics
JNK Mitogen-Activated Protein Kinases metabolism
Ketone Bodies genetics
Ketone Bodies metabolism
Male
Middle Aged
Mitochondria, Liver genetics
Mitochondria, Liver pathology
Mitochondrial Membrane Transport Proteins
PPAR alpha genetics
RNA, Messenger biosynthesis
RNA, Messenger genetics
Triglycerides genetics
Triglycerides metabolism
Citrullinemia metabolism
Down-Regulation
Fatty Liver metabolism
Lipid Metabolism
Mitochondria, Liver metabolism
PPAR alpha biosynthesis
Subjects
Details
- Language :
- English
- ISSN :
- 0006-3002
- Volume :
- 1852
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Biochimica et biophysica acta
- Publication Type :
- Academic Journal
- Accession number :
- 25533124
- Full Text :
- https://doi.org/10.1016/j.bbadis.2014.12.011