The Nutrient-Dependent O-GlcNAc Modification Controls the Expression of Liver Fatty Acid Synthase - Université de Lille Accéder directement au contenu
Article Dans Une Revue Journal of Molecular Biology Année : 2016

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

Résumé

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.
Fichier non déposé

Dates et versions

hal-03285077 , version 1 (13-07-2021)

Identifiants

Citer

Steffi F. Baldini, Cindy Wavelet, Isabelle Hainault, Céline Guinez, Tony Lefebvre. The Nutrient-Dependent O-GlcNAc Modification Controls the Expression of Liver Fatty Acid Synthase. Journal of Molecular Biology, 2016, Journal of Molecular Biology, 428 (16), pp.3295-3304. ⟨10.1016/j.jmb.2016.04.035⟩. ⟨hal-03285077⟩
17 Consultations
0 Téléchargements

Altmetric

Partager

Gmail Mastodon Facebook X LinkedIn More