The Nutrient-Dependent O-GlcNAc Modification Controls the Expression of Liver Fatty Acid Synthase

Autor: Isabelle Hainault, Steffi F. Baldini, Céline Guinez, Tony Lefebvre, Cindy Wavelet
Přispěvatelé: Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576 (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche des Cordeliers (CRC), Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Environnement périnatal et croissance - EA 4489 (EPS), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université de Lille, LillOA, Institut National de la Recherche Agronomique (INRA)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Jazyk: angličtina
Rok vydání: 2016
Předmět:
0301 basic medicine
medicine.medical_specialty
Inbred C57BL
N-Acetylglucosaminyltransferases
Cell Line
03 medical and health sciences
Mice
0302 clinical medicine
O-GlcNAcylation
Structural Biology
Internal medicine
medicine
Animals
Obesity
ob/ob mice
Liver X receptor
Carbohydrate-responsive element-binding protein
Molecular Biology
Protein Processing
biology
Liver cell
Lipogenesis
Post-Translational
FAS
medicine.disease
Sterol regulatory element-binding protein
Mice
Inbred C57BL
[CHIM.THEO]Chemical Sciences/Theoretical and/or physical chemistry
[CHIM.THEO] Chemical Sciences/Theoretical and/or physical chemistry
Metabolic pathway
Fatty acid synthase
030104 developmental biology
Endocrinology
Liver
Food
030220 oncology & carcinogenesis
biology.protein
Steatosis
Fatty Acid Synthases
Protein Processing
Post-Translational
Zdroj: Journal of Molecular Biology
Journal of Molecular Biology, 2016, Journal of Molecular Biology, 428 (16), pp.3295-3304. ⟨10.1016/j.jmb.2016.04.035⟩
ISSN: 1089-8638
Popis: International audience; Liver Fatty Acid Synthase (FAS) is pivotal for de novo lipogenesis. Loss of control of this metabolic pathway contributes to the development of liver pathologies ranging from steatosis to nonalcoholic steatohepatitis (NASH) which can lead to cirrhosis and, less frequently, to hepatocellular carcinoma. Therefore, deciphering the molecular mechanisms governing the expression and function of key enzymes such as FAS is crucial. Herein, we link the availability of this lipogenic enzyme to the nutrient-dependent post-translational modification O-GlcNAc that is thought to be deregulated in metabolic diseases (diabetes, obesity, and metabolic syndrome). We demonstrate that expression and activity of liver FAS correlate with O-GlcNAcylation contents in ob/ob mice and in mice fed with a high-carbohydrate diet both in a transcription-dependent and -independent manner. More importantly, inhibiting the removal of O-GlcNAc residues in mice intraperitoneally injected with the selective and potent O-GlcNAcase (OGA) inhibitor Thiamet-G increases FAS expression. FAS and O-GlcNAc transferase (OGT) physically interact, and FAS is O-GlcNAc modified. Treatment of a liver cell line with drugs or nutrients that elevate the O-GlcNAcylation interferes with FAS expression. Inhibition of OGA increases the interaction between FAS and the deubiquitinase Ubiquitin-specific protease-2a (USP2A) in vivo and ex vivo, providing mechanistic insights into the control of FAS expression through O-GlcNAcylation. Together, these results reveal a new type of regulation of FAS, linked to O-GlcNAcylation status, and advance our knowledge on deregulation of lipogenesis in diverse forms of liver diseases.
Databáze: OpenAIRE
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