title: The Nutrient-Dependent O-GlcNAc Modification Controls the Expression of Liver Fatty Acid Synthase.
abstract: 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.
authors.affiliation: Univ. Lille, CNRS, UMR 8576, UGSF, Unité de Glycobiologie Structurale et Fonctionnelle, 59000 Lille, France.
authors.forename: Steffi F
authors.initials: SF
authors.lastname: Baldini
authors.affiliation: Univ. Lille, CNRS, UMR 8576, UGSF, Unité de Glycobiologie Structurale et Fonctionnelle, 59000 Lille, France.
authors.forename: Cindy
authors.initials: C
authors.lastname: Wavelet
authors.affiliation: Institute of Cardiometabolism and Nutrition, Université Pierre et Marie Curie, INSERM, UMR_S1138, Centre de Recherche des Cordeliers, 75006 Paris, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Hainault
authors.affiliation: Univ. Lille, EA4489, Environnement Périnatal et Croissance, Equipe dénutritions maternelles périnatales, 59000 Lille, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Guinez
authors.affiliation: Univ. Lille, CNRS, UMR 8576, UGSF, Unité de Glycobiologie Structurale et Fonctionnelle, 59000 Lille, France. Electronic address: tony.lefebvre@univ-lille1.fr.
authors.forename: Tony
authors.initials: T
authors.lastname: Lefebvre
mesh_terms: D000818:Animals; D002460:Cell Line; D064429:Fatty Acid Synthases / Q000378:metabolism*; D005502:Food; D050155:Lipogenesis / Q000502:physiology; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D017351:N-Acetylglucosaminyltransferases / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000502:physiology
chemical_list: D064429:Fatty Acid Synthases; D017351:N-Acetylglucosaminyltransferases; C449880:O-GlcNAc transferase
keywords: FAS; O-GlcNAcylation; lipogenesis; liver; ob/ob mice