| Summary: | 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><sup>∆Hep</sup> mice). In this study, we report that <i>Napepld</i><sup>∆Hep</sup> mice develop a high-fat diet-like phenotype, characterized by an increased fat mass gain, hepatic steatosis and we show that <i>Napepld</i><sup>∆Hep</sup> 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.
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