Abstract
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 restricted to the gastrointestinal tract, but can affect different tissues throughout the organism. It is still unclear whether these effects also involve signaling of bile acids to the central nervous system (CNS). Bile acid signaling to the CNS encompasses both direct and indirect pathways. Bile acids can act directly in the brain via central FXR and TGR5 signaling. In addition, there are two indirect pathways that involve intermediate agents released upon interaction with bile acids receptors in the gut. Activation of intestinal FXR and TGR5 receptors can result in the release of fibroblast growth factor 19 (FGF19) and glucagon-like peptide 1 (GLP-1), both capable of signaling to the CNS. We conclude that when plasma bile acids levels are high all three pathways may contribute in signal transmission to the CNS. However, under normal physiological circumstances, the indirect pathway involving GLP-1 may evoke the most substantial effect in the brain.
Highlights
Bile acids are synthesized in the liver from cholesterol and released in the intestinal lumen upon food intake
A recent study showed that microglial cells express Takeda G protein-coupled receptor 5 (TGR5) and that binding of taurineconjugated ursodeoxycholic acid (UDCA) (TUDCA) to TGR5 has anti-inflammatory effects in a mouse model of acute brain inflammation (YanguasCasás et al, 2017). This could explain the neuroprotective effects of TUDCA observed as reduced neuronal apoptosis in several animal models for neurodegenerative diseases, such as Huntington’s disease (Keene et al, 2001, 2002), Alzheimer’s disease (Sola et al, 2006; Viana et al, 2009), Parkinson’s disease (Duan et al, 2002), acute ischemia (Rodrigues et al, 2002), and hemorrhagic stroke (Rodrigues et al, 2003). These findings highlight the physiological differences of bile acid species, where deoxycholic acid (DCA) and chenodeoxycholic acid (CDCA) interfere and disturb gap junction function in the blood-brain barrier (BBB), but UDCA and its conjugated forms exert a protective effect on brain endothelial cells and neurons
Rats on a high fat diet (HFD) showed reduced expression of hypothalamic FGFR1 and 4 compared to chow-fed rats (Ryan et al, 2013). These findings suggest that central FGFR signaling is involved in energy and glucose metabolism
Summary
Bile acids are synthesized in the liver from cholesterol and released in the intestinal lumen upon food intake. These findings highlight the physiological differences of bile acid species, where DCA and CDCA interfere and disturb gap junction function in the BBB, but UDCA and its conjugated forms exert a protective effect on brain endothelial cells and neurons. INDIRECT BILE ACID SIGNALING TO THE CENTRAL NERVOUS SYSTEM VIA FXR-FGF15/19 PATHWAY
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