Bile Acid Signaling Pathways from the Enterohepatic Circulation to the Central Nervous System

REVIEW published: 07 November 2017 doi: 10.3389/fnins.2017.00617 Bile Acid Signaling Pathways from the Enterohepatic Circulation to the Central Nervous System Kim L. Mertens 1, Andries Kalsbeek 2, 3, 4, Maarten R. Soeters 2 and Hannah M. Eggink 2, 4* 1 Master’s Program in Biomedical Sciences, University of Amsterdam, Amsterdam, Netherlands, 2 Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands, 3 Laboratory of Endocrinology, Department Clinical Chemistry, Academic Medical Centre, University of Amsterdam, Amsterdam, Netherlands, 4 Department of Hypothalamic Integration Mechanisms, Netherlands Institute for Neuroscience, Amsterdam, Netherlands Bile acids are best known as detergents involved in the digestion of lipids. In addition, new data in the last decade have shown that bile acids also function as gut hormones capable of influencing metabolic processes via receptors such as FXR (farnesoid X receptor) and TGR5 (Takeda G protein-coupled receptor 5). These effects of bile acids are not Edited by: restricted to the gastrointestinal tract, but can affect different tissues throughout the Miguel López, Universidade de Santiago de organism. It is still unclear whether these effects also involve signaling of bile acids to Compostela, Spain the central nervous system (CNS). Bile acid signaling to the CNS encompasses both Reviewed by: direct and indirect pathways. Bile acids can act directly in the brain via central FXR and Angel Nadal, TGR5 signaling. In addition, there are two indirect pathways that involve intermediate Universidad Miguel Hernández de Elche, Spain agents released upon interaction with bile acids receptors in the gut. Activation of Joseph Pisegna, intestinal FXR and TGR5 receptors can result in the release of fibroblast growth factor 19 University of California, Los Angeles, United States (FGF19) and glucagon-like peptide 1 (GLP-1), both capable of signaling to the CNS. We *Correspondence: conclude that when plasma bile acids levels are high all three pathways may contribute Hannah M. Eggink in signal transmission to the CNS. However, under normal physiological circumstances, [email protected] the indirect pathway involving GLP-1 may evoke the most substantial effect in the brain. Specialty section: Keywords: bile acids, CNS, brain, FXR, FGF19, TGR5, GLP-1 This article was submitted to Neuroendocrine Science, a section of the journal INTRODUCTION Frontiers in Neuroscience Received: 07 July 2017 Bile acids are synthesized in the liver from cholesterol and released in the intestinal lumen upon Accepted: 23 October 2017 food intake. They are predominantly known for their role as nutritional detergents that dissolve Published: 07 November 2017 lipids and lipid-soluble vitamins. However, a growing body of recent literature describes bile Citation: acids as versatile signaling molecules (Houten et al., 2006; de Aguiar Vallim et al., 2013; Kuipers Mertens KL, Kalsbeek A, Soeters MR et al., 2014), with a widespread distribution of bile acid receptors throughout the organism. Via and Eggink HM (2017) Bile Acid these receptors, bile acids are capable of modulating their own synthesis (Chiang, 2009; Lefebvre Signaling Pathways from the Enterohepatic Circulation to the et al., 2009), lipid, glucose and energy metabolism (Thomas et al., 2008a,b; Lefebvre et al., 2009; Central Nervous System. Schonewille et al., 2016). In addition, bile acids can signal via intermediate signaling molecules that Front. Neurosci. 11:617. are released upon activation of bile acid receptors in the intestine. The receptors receptive for these doi: 10.3389/fnins.2017.00617 intermediate molecules are also distributed ubiquitously throughout the body. Frontiers in Neuroscience | www.frontiersin.org 1 November 2017 | Volume 11 | Article 617 Mertens et al. Bile Acid Signaling to the Brain Bile acids and their associated receptors have been detected in in a daily rhythm associated with food intake that fluctuates the human and rodent brain (Mano et al., 2004a; Ferdinandusse between 5 and 15 µM in humans (Angelin and Bjorkhem, 1977; et al., 2009; Keitel et al., 2010; Huang et al., 2016; McMillin LaRusso et al., 1978; Schalm et al., 1978; Glicksman et al., et al., 2016; Zheng et al., 2016), however, it is still not clear 2010; Steiner et al., 2011; Sonne et al., 2016). Also in rodents whether bile acids are capable of signaling to the central nervous a daily rhythm of plasma bile acid levels has been reported system (CNS) and what this signaling could imply. Two recent (Ho, 1976a,b; Zhang et al., 2011; Eggink et al., 2017). These reviews discussed the role of bile acids in neurological diseases feeding-induced changes indicate that circulating bile acids could (Ackerman and Gerhard, 2016; McMillin and DeMorrow, 2016), provide a postprandial signal, transmitting information about but did not elaborate on the possible physiological effects of the arrival of nutrients and the subsequent availability of energy bile acid signaling. Therefore, in this review we discuss the (Thomas et al., 2008a). In addition, hepatocytes are equipped signaling pathways of bile acids implicated in the control of with a machinery that can actively promote bile acid excretion energy metabolism under normal physiological circumstances, when hepatic bile acid concentration increase extensively, as involving both direct and indirect pathways to the CNS. accumulating bile acids can be toxic due to their detergent-like function (Zollner et al., 2006). Consequently, many cases of liver failure or liver damage result in an increased efflux of bile acids BILE ACID METABOLISM AND THE into the systemic circulation, leading to high levels of plasma bile ENTEROHEPATIC CIRCULATION acids (Neale et al., 1971; Engelking et al., 1980; Benyoub et al., 2011; Tanaka et al., 2012; Quinn et al., 2014; McMillin et al., Bile acid synthesis and enterohepatic cycling have been 2016). elaborately reviewed previously (Russell, 2003; Thomas et al., 2008b). In short, bile acids have a cholesterol backbone. Bile acid biosynthesis mainly occurs in hepatocytes (Figure 1), where BILE ACIDS AND THE BLOOD-BRAIN the classical pathway is initiated by cholesterol 7α-hydroxylase BARRIER (CYP7A1) which is regulated by the farnesoid X receptor (FXR). The alternative pathway can be initiated by different enzymes Once in the systemic circulation, bile acids reach the brain via the that are also expressed outside the liver. De novo synthesized bile internal carotid and vertebral arteries that join in an artery ring at acids are called primary bile acids. In humans the primary bile the base of the brain—the circle of Willis. From here the arteries acids are cholic acid (CA) and chenodeoxycholic acid (CDCA); arise that ensure blood supply to the brain. In contrast with other in mice the dominant bile acids are CA and muricholic acid capillaries throughout the body, brain capillary endothelial cells (MCA). Subsequently, these bile acids are conjugated with the are interconnected by tight junctions so substances in the blood amino acids glycine (mainly in humans) or taurine (mainly in need to cross the endothelial cell membranes in order to enter mice). Bile acids are transported from the hepatocytes through the brain. This blood-brain barrier (BBB) protects the brain from the bile canaliculi and stored, together with cholesterol and potentially harmful circulating molecules (Bernacki et al., 2008; phospholipids, in the gallbladder. Following food intake, the Abbott et al., 2010). presence of nutrients (especially fats and proteins) in the stomach There are reports that both unconjugated and conjugated triggers gallbladder emptying which results in the release of bile bile acids can cross the BBB (Keene et al., 2001; Palmela et al., acids into the duodenum. When bile acids pass through the 2015; McMillin et al., 2016; Figure 3A), however, the involved intestinal tract, they contribute to the absorption of lipids and mechanisms are still uncertain. Unconjugated bile acids might fat-soluble vitamins. In the intestine, gut microbiota deconjugate diffuse across the BBB, because CA, CDCA, and deoxycholic and dehydroxylate the primary bile acids, converting them into acid (DCA) are capable of diffusing across phospholipid bilayers secondary bile acids and enhancing the diversity of the bile (Kamp and Hamilton, 1993) and their brain levels correlate with acid pool (Figure 1). In the jejunum and colon, unconjugated, their serum levels (Higashi et al., 2017). Indeed, unconjugated and uncharged bile acids enter the enterocytes through passive ursodeoxycholic acid (UDCA) crossed the BBB in a dose depend diffusion (Figure 2). In the ileum, active uptake of conjugated manner in orally treated amyotrophic lateral sclerosis patients bile acids takes place by the apical sodium-dependent bile acid (Parry et al., 2010). Conjugated bile acids need active transport transporter (ASBT). In total about 95% of the bile acids are to cross the BBB due to their larger structure and amphipathic reabsorbed into intestinal enterocytes. The remaining 5% is nature (St-Pierre et al., 2001). Indeed, several xenobiotic and excreted via feces, a loss which is compensated for by de novo bile acid transporters found in the liver, intestine, and kidney bile acid synthesis in the liver. Specific transporters in enterocytes are also present at the BBB and choroid plexus providing make sure that bile acids are redirected to the liver via the portal the machinery for bile acid transport over the BBB. These vein. In the liver, about ∼90% of the bile acids are cleared from include members of the solute carrier (SLC) family such as the hepatic circulation for reuse. Bile acids can be recycled 4–12 the organic anion transporting polypeptides (OATP) and ASBT, times per day between hepatocytes in the liver and enterocytes in and members of the ATP-binding cassette transporters (ABC) the intestine—which is called the enterohepatic circulation(Mok family such as the multidrug resistance protein (MRD) 2 and et al., 1977; Figure 2). Only a small portion (<10%) of the total 4 (Choudhuri et al., 2003; Bernacki et al., 2008; Abbott et al., bile acid pool reaches the systemic circulation.

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