The Liver under the Spotlight: Bile Acids and Oxysterols as Pivotal Actors Controlling Metabolism.

Among the myriad of molecules produced by the liver, both bile acids and their precursors, the oxysterols are becoming pivotal bioactive lipids which have been underestimated for a long time. Their actions are ranging from regulation of energy homeostasis (i.e., glucose and lipid metabolism) to inflammation and immunity, thereby opening the avenue to new treatments to tackle metabolic disorders associated with obesity (e.g., type 2 diabetes and hepatic steatosis) and inflammatory diseases. Here, we review the biosynthesis of these endocrine factors including their interconnection with the gut microbiota and their impact on host homeostasis as well as their attractive potential for the development of therapeutic strategies for metabolic disorders.

Intestinal NAPE-PLD contributes to short-term regulation of food intake via gut-to-brain axis.

Our objective was to explore the physiological role of the intestinal endocannabinoids in the regulation of appetite upon short-term exposure to high-fat-diet (HFD) and understand the mechanisms responsible for aberrant gut-brain signaling leading to hyperphagia in mice lacking Napepld in the intestinal epithelial cells (IECs). We generated a murine model harboring an inducible NAPE-PLD deletion in IECs (NapepldΔIEC). After an overnight fast, we exposed wild-type (WT) and NapepldΔIEC mice to different forms of lipid challenge (HFD or gavage), and we compared the modification occurring in the hypothalamus, in the vagus nerve, and at endocrine level 30 and 60 min after the stimulation. NapepldΔIEC mice displayed lower hypothalamic levels of N-oleoylethanolamine (OEA) in response to HFD. Lower mRNA expression of anorexigenic Pomc occurred in the hypothalamus of NapepldΔIEC mice after lipid challenge. This early hypothalamic alteration was not the consequence of impaired vagal signaling in NapepldΔIEC mice. Following lipid administration, WT and NapepldΔIEC mice had similar portal levels of glucagon-like peptide-1 (GLP-1) and similar rates of GLP-1 inactivation. Administration of exendin-4, a full agonist of GLP-1 receptor (GLP-1R), prevented the hyperphagia of NapepldΔIEC mice upon HFD. We conclude that in response to lipid, NapepldΔIEC mice displayed reduced OEA in brain and intestine, suggesting an impairment of the gut-brain axis in this model. We speculated that decreased levels of OEA likely contributes to reduce GLP-1R activation, explaining the observed hyperphagia in this model. Altogether, we elucidated novel physiological mechanisms regarding the gut-brain axis by which intestinal NAPE-PLD regulates appetite rapidly after lipid exposure.

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

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.

Hepatic MyD88 regulates liver inflammation by altering synthesis of oxysterols.

This study aimed to investigate the function of hepatic myeloid differentiation primary response gene 88 (MyD88), a central adaptor of innate immunity, in metabolism. Although its role in inflammation is well known, we have recently discovered that MyD88 can also mediate energy, lipid, and glucose metabolism. More precisely, we have reported that mice harboring hepatocyte-specific deletion of MyD88 (Myd88ΔHep) were predisposed to glucose intolerance, liver fat accumulation, and inflammation. However, the molecular events explaining the onset of hepatic disorders and inflammation remain to be elucidated. To investigate the molecular mechanism, Myd88ΔHep and wild-type (WT) mice were challenged by two complementary approaches affecting liver lipid metabolism and immunity. The first approach consisted of a short-term exposure to high-fat diet (HFD), whereas the second was an acute LPS injection. We discovered that upon 3 days of HFD Myd88ΔHep mice displayed an increase in liver weight and liver lipids compared with WT mice. Moreover, we found that bile acid and oxysterol metabolism were deeply affected by the absence of hepatic MyD88. Our data suggest that the negative feedback loop suppressing bile acid synthesis was impaired (i.e., ERK activity was decreased) in Myd88ΔHep mice. Finally, the predisposition to inflammation sensitivity displayed by Myd88ΔHep mice may be caused by the accumulation of 25-hydroxycholesterol, an oxysterol linked to inflammatory response and metabolic disorders. This study highlights the importance of MyD88 on both liver fat accumulation and cholesterol-derived bioactive lipid synthesis. These are two key features associated with metabolic syndrome. Therefore, investigating the regulation of hepatic MyD88 could lead to discovery of new therapeutic targets.

Microbial regulation of organismal energy homeostasis.

The gut microbiome has emerged as a key regulator of host metabolism. Here we review the various mechanisms through which the gut microbiome influences the energy metabolism of its host, highlighting the complex interactions between gut microbes, their metabolites and host cells. Among the most important bacterial metabolites are short-chain fatty acids, which serve as a direct energy source for host cells, stimulate the production of gut hormones and act in the brain to regulate food intake. Other microbial metabolites affect systemic energy expenditure by influencing thermogenesis and adipose tissue browning. Both direct and indirect mechanisms of action are known for specific metabolites, such as bile acids, branched chain amino acids, indole propionic acid and endocannabinoids. We also discuss the roles of specific bacteria in the production of specific metabolites and explore how external factors, such as antibiotics and exercise, affect the microbiome and thereby energy homeostasis. Collectively, we present a large body of evidence supporting the concept that gut microbiota-based therapies can be used to modulate host metabolism, and we expect to see such approaches moving from bench to bedside in the near future.