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ITCH E3 ubiquitin ligase downregulation compromises hepatic degradation of branched-chain amino acids
R. Menghini, L. Hoyles, M. Cardellini, V. Casagrande, A. Marino, P. Gentileschi, F. Davato, M. Mavilio, I. Arisi, A. Mauriello, M. Montanaro, M. Scimeca, RH. Barton, F. Rappa, F. Cappello, M. Vinciguerra, JM. Moreno-Navarrete, W. Ricart, O....
Jazyk angličtina Země Německo
Typ dokumentu časopisecké články, práce podpořená grantem
Grantová podpora
MR/L01632X/1
Medical Research Council - United Kingdom
Department of Health - United Kingdom
NLK
Directory of Open Access Journals
od 2012
Free Medical Journals
od 2012
PubMed Central
od 2012
Open Access Digital Library
od 2012-01-01
Open Access Digital Library
od 2012-12-01
ROAD: Directory of Open Access Scholarly Resources
od 2012
- MeSH
- down regulace MeSH
- lidé MeSH
- myši knockoutované MeSH
- myši MeSH
- nádory jater * MeSH
- nealkoholová steatóza jater * MeSH
- obezita * komplikace MeSH
- ubikvitinligasy * genetika metabolismus MeSH
- větvené aminokyseliny * metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
OBJECTIVE: Metabolic syndrome, obesity, and steatosis are characterized by a range of dysregulations including defects in ubiquitin ligase tagging proteins for degradation. The identification of novel hepatic genes associated with fatty liver disease and metabolic dysregulation may be relevant to unravelling new mechanisms involved in liver disease progression METHODS: Through integrative analysis of liver transcriptomic and metabolomic obtained from obese subjects with steatosis, we identified itchy E ubiquitin protein ligase (ITCH) as a gene downregulated in human hepatic tissue in relation to steatosis grade. Wild-type or ITCH knockout mouse models of non-alcoholic fatty liver disease (NAFLD) and obesity-related hepatocellular carcinoma were analyzed to dissect the causal role of ITCH in steatosis RESULTS: We show that ITCH regulation of branched-chain amino acids (BCAAs) degradation enzymes is impaired in obese women with grade 3 compared with grade 0 steatosis, and that ITCH acts as a gatekeeper whose loss results in elevation of circulating BCAAs associated with hepatic steatosis. When ITCH expression was specifically restored in the liver of ITCH knockout mice, ACADSB mRNA and protein are restored, and BCAA levels are normalized both in liver and plasma CONCLUSIONS: Our data support a novel functional role for ITCH in the hepatic regulation of BCAA metabolism and suggest that targeting ITCH in a liver-specific manner might help delay the progression of metabolic hepatic diseases and insulin resistance.
Center for Atherosclerosis University Hospital Policlinico Tor Vergata Italy
CIBER Fisiopatologia de la Obesidad y Nutricion Girona Spain
CNR Institute of Translational Pharmacology Via del Fosso del Cavaliere 100 00131 Rome Italy
Department of Biosciences Nottingham Trent University Nottingham NG11 8NS United Kingdom
Department of Medical Sciences School of Medicine University of Girona Spain
Department of Surgery University of Rome Tor Vergata Via Montpellier 1 00133 Rome Italy
Department of Systems Medicine University of Rome Tor Vergata Via Montpellier 1 00133 Rome Italy
Euro Mediterranean Institute of Science and Technology Palermo Italy
European Brain Research Institute Rita Levi Montalcini Viale Regina Elena 295 00161 Rome Italy
International Clinical Research Center St Anne University Hospital Brno Czech Republic
Citace poskytuje Crossref.org
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- $a OBJECTIVE: Metabolic syndrome, obesity, and steatosis are characterized by a range of dysregulations including defects in ubiquitin ligase tagging proteins for degradation. The identification of novel hepatic genes associated with fatty liver disease and metabolic dysregulation may be relevant to unravelling new mechanisms involved in liver disease progression METHODS: Through integrative analysis of liver transcriptomic and metabolomic obtained from obese subjects with steatosis, we identified itchy E ubiquitin protein ligase (ITCH) as a gene downregulated in human hepatic tissue in relation to steatosis grade. Wild-type or ITCH knockout mouse models of non-alcoholic fatty liver disease (NAFLD) and obesity-related hepatocellular carcinoma were analyzed to dissect the causal role of ITCH in steatosis RESULTS: We show that ITCH regulation of branched-chain amino acids (BCAAs) degradation enzymes is impaired in obese women with grade 3 compared with grade 0 steatosis, and that ITCH acts as a gatekeeper whose loss results in elevation of circulating BCAAs associated with hepatic steatosis. When ITCH expression was specifically restored in the liver of ITCH knockout mice, ACADSB mRNA and protein are restored, and BCAA levels are normalized both in liver and plasma CONCLUSIONS: Our data support a novel functional role for ITCH in the hepatic regulation of BCAA metabolism and suggest that targeting ITCH in a liver-specific manner might help delay the progression of metabolic hepatic diseases and insulin resistance.
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