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

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-GIcNAc 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-GIcNAcylation 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-GIcNAc residues in mice intraperitoneally injected with the selective and potent O-GIcNAcase (OGA) inhibitor Thiamet-G increases FAS expression. FAS and O-GIcNAc transferase (OGT) physically interact, and FAS is O-GIcNAc modified. Treatment of a liver cell line with drugs or nutrients that elevate the O-GIcNAcylation 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-GIcNAcylation. Together, these results reveal a new type of regulation of FAS, linked to O-GIcNAcylation status, and advance our knowledge on deregulation of lipogenesis in diverse forms of liver diseases. (C) 2016 Elsevier Ltd. All rights reserved.