ArticleBiochimica et biophysica acta2015
Steatogenesis in adult-onset type II citrullinemia is associated with down-regulation of PPARα.
Article in Biochimica et biophysica acta, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers.
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Who cites it
46 citing papers in PubMed, 73 citations in OpenAlex.
- Integrative multi-omics analysis identifies stellate cell-derived complement component 7 as a predictor of fibrosis and liver-related events in MASLD.JHEP reports : innovation in hepatology · 2026Article
- Effect of Dotinurad on Uric Acid and Hepatorenal Parameters in Steatotic Liver Disease: A Pilot Study in Japanese Patients.Biomedicines · 2025Article
- Developing an explainable machine learning model to predict false-negative citrin deficiency cases in newborn screening.Orphanet journal of rare diseases · 2025Article
- Metabolic signatures and a diagnostic model for citrin deficiency based on urinary organic acids.Clinical and translational medicine · 2025Article
- Metabolic profiles and prediction of failure to thrive of citrin deficiency with normal liver function based on metabolomics and machine learning.Nutrition & metabolism · 2025Article
- Current Understanding of Pathogenic Mechanisms and Disease Models of Citrin Deficiency.Journal of inherited metabolic disease · 2025Review
- A crucial role of the malate aspartate shuttle in metabolic reprogramming in TNF-induced SIRS.Frontiers in immunology · 2025Article
- My path to citrin deficiency.Journal of inherited metabolic disease · 2025Review
- Citrin deficiency-The East-side story.Journal of inherited metabolic disease · 2024Review
- The therapeutic landscape of citrin deficiency.Journal of inherited metabolic disease · 2024Review
- Pathogenesis and Management of Citrin Deficiency.Internal medicine (Tokyo, Japan) · 2024Review
- Serum autotaxin is a prognostic indicator of liver-related events in patients with non-alcoholic fatty liver disease.Communications medicine · 2024Article
- Long-Term pemafibrate treatment exhibits limited impact on body fat mass in patients with hypertriglyceridemia accompanying NAFLD.Frontiers in endocrinology · 2024Article
- Hepatic insulin receptor: new views on the mechanisms of liver disease.Metabolism: clinical and experimental · 2023Review
- Loss of hepatic PPARα in mice causes hypertension and cardiovascular disease.American journal of physiology. Regulatory, integrative and comparative physiology · 2023Article
- Nicotinamide riboside rescues dysregulated glycolysis and fatty acid β-oxidation in a human hepatic cell model of citrin deficiency.Human molecular genetics · 2023Article
- Citrin Deficiency: Clinical and Nutritional Features.Nutrients · 2023Review
- Higher Responsiveness for Women, High Transaminase Levels, and Fat Percentage to Pemafibrate Treatment for NAFLD.Biomedicines · 2022Article
- Pathogenic variants of the mitochondrial aspartate/glutamate carrier causing citrin deficiency.Trends in endocrinology and metabolism: TEM · 2022Review
- Obstacles to home-based dietary management for caregivers of children with citrin deficiency: a qualitative study.Orphanet journal of rare diseases · 2022Article
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Authors and funding
15 authors at 4 institutions in 3 countries.
Funding
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.
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