Hepatic NAPE-PLD Is a Key Regulator of Liver Lipid Metabolism

• Main Authors: Charlotte Lefort, Martin Roumain, Matthias Van Hul, Marialetizia Rastelli, Rita Manco, Isabelle Leclercq, Nathalie M. Delzenne, Vincenzo Di Marzo, Nicolas Flamand, Serge Luquet, Cristoforo Silvestri, Giulio G. Muccioli, Patrice D. Cani
• Format: Article
• Language: English
• Published: MDPI AG 2020-05-01
• Series: Cells
• Subjects: NAPE-PLD; NAEs; bioactive lipids; bile acids; inflammation; liver
• Online Access: https://www.mdpi.com/2073-4409/9/5/1247

Diverse metabolic disorders have been associated with an alteration of <i>N</i>-acylethanolamine (NAE) levels. These bioactive lipids are synthesized mainly by <i>N</i>-acylphosphatidylethanolamine-selective phospholipase D (NAPE-PLD) and influence host metabolism. We have previously discovered that NAPE-PLD in the intestine and adipose tissue is connected to the pathophysiology of obesity. However, the physiological function of NAPE-PLD in the liver remains to be deciphered. To study the role of liver NAPE-PLD on metabolism, we generated a new mouse model of inducible <i>Napepld</i> hepatocyte-specific deletion (<i>Napepld</i>^∆Hep mice). In this study, we report that <i>Napepld</i>^∆Hep mice develop a high-fat diet-like phenotype, characterized by an increased fat mass gain, hepatic steatosis and we show that <i>Napepld</i>^∆Hep mice are more sensitive to liver inflammation. We also demonstrate that the role of liver NAPE-PLD goes beyond the mere synthesis of NAEs, since the deletion of NAPE-PLD is associated with a marked modification of various bioactive lipids involved in host homeostasis such as oxysterols and bile acids. Collectively these data suggest that NAPE-PLD in hepatocytes is a key regulator of liver bioactive lipid synthesis and a dysregulation of this enzyme leads to metabolic complications. Therefore, deepening our understanding of the regulation of NAPE-PLD could be crucial to tackle obesity and related comorbidities.