Abstract
Diverse metabolic disorders have been associated with an alteration of N-acylethanolamine (NAE) levels. These bioactive lipids are synthesized mainly by N-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 Napepld hepatocyte-specific deletion (Napepld∆Hep mice). In this study, we report that Napepld∆Hep mice develop a high-fat diet-like phenotype, characterized by an increased fat mass gain, hepatic steatosis and we show that Napepld∆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.
Highlights
Over the last few years, interest in specific bioactive lipids, the N-acylethanolamines (NAEs), has increased exponentially as accumulating evidence demonstrated an association between variations in NAE levels and diverse pathological conditions such as obesity, inflammation or hepatic disorders [1,2,3]
Almost all the lipid congeners related to the eCBome were affected in the liver of Napepld∆Hep mice, suggesting that NAPE-PLD could, albeit indirectly, control the biosynthesis of a larger group of bioactive lipids in the liver than initially thought (Figure 1C and Figure S1B)
The bioactive lipids belonging to the eCBome are involved in numerous metabolic functions, including lipid and glucose metabolism, energy homeostasis and regulation of inflammatory tone [2,40]
Summary
Over the last few years, interest in specific bioactive lipids, the N-acylethanolamines (NAEs), has increased exponentially as accumulating evidence demonstrated an association between variations in NAE levels and diverse pathological conditions such as obesity, inflammation or hepatic disorders [1,2,3]. Recent studies have made progress in that perspective and have elegantly shown that natural bile acids, and specific steroidal hydroxylation pattern were key elements for modulating the enzyme activity [13]. These data suggesting a link between NAPE-PLD and steroid acids open the floor to design putative small-molecule modulators with potential therapeutic applications [14]
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