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Bile Acids and GPBAR-1: Dynamic Interaction Involving Genes, Environment and Gut Microbiome

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nutrients Review Bile Acids and GPBAR-1: Dynamic Interaction Involving Genes, Environment and Gut Microbiome 1, , 1, 2, 3 Piero Portincasa * y , Agostino Di Ciaula y , Gabriella Garruti y, Mirco Vacca , Maria De Angelis 3 and David Q.-H. Wang 4 1 Clinica Medica “A. Murri”, Department of Biomedical Sciences & Human Oncology, University of Bari Medical School, 70124 Bari, Italy; [email protected] 2 Section of Endocrinology, Department of Emergency and Organ Transplantations, University of Bari “Aldo Moro” Medical School, Piazza G. Cesare 11, 70124 Bari, Italy; [email protected] 3 Dipartimento di Scienze del Suolo, Della Pianta e Degli Alimenti, Università degli Studi di Bari Aldo Moro, 70124 Bari, Italy; [email protected] (M.V.); [email protected] (M.D.A.) 4 Department of Medicine and Genetics, Division of Gastroenterology and Liver Diseases, Marion Bessin Liver Research Center, Einstein-Mount Sinai Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA; [email protected] * Correspondence: [email protected]; Tel.: +39-80-5478-893 These authors contributed equally to this work. y Received: 3 November 2020; Accepted: 26 November 2020; Published: 30 November 2020 Abstract: Bile acids (BA) are amphiphilic molecules synthesized in the liver from cholesterol. BA undergo continuous enterohepatic recycling through intestinal biotransformation by gut microbiome and reabsorption into the portal tract for uptake by hepatocytes. BA are detergent molecules aiding the digestion and absorption of dietary fat and fat-soluble vitamins, but also act as important signaling molecules via the nuclear receptor, farnesoid X receptor (FXR), and the membrane-associated G protein-coupled bile acid receptor 1 (GPBAR-1) in the distal intestine, liver and extra hepatic tissues. The hydrophilic-hydrophobic balance of the BA pool is finely regulated to prevent BA overload and liver injury. By contrast, hydrophilic BA can be hepatoprotective. The ultimate effects of BA-mediated activation of GPBAR-1 is poorly understood, but this receptor may play a role in protecting the remnant liver and in maintaining biliary homeostasis. In addition, GPBAR-1 acts on pathways involved in inflammation, biliary epithelial barrier permeability, BA pool hydrophobicity, and sinusoidal blood flow. Recent evidence suggests that environmental factors influence GPBAR-1 gene expression. Thus, targeting GPBAR-1 might improve liver protection, facilitating beneficial metabolic effects through primary prevention measures. Here, we discuss the complex pathways linked to BA effects, signaling properties of the GPBAR-1, mechanisms of liver damage, gene-environment interactions, and therapeutic aspects. Keywords: bile; cholestasis; FXR; metabolic syndrome; nuclear receptors; TGR5; thermogenesis 1. Introduction Bile acids (BA) are amphipathic molecules made from cholesterol in the liver in the pericentral hepatocytes. BA are conjugated to taurine or glycine to increase their solubility, are actively secreted into the bile canaliculus, and become the major lipid components of bile. During fasting, bile is mostly diverted and stored in the gallbladder, where water is reabsorbed, and bile concentration occurs. During the interprandial phase, a low-grade secretion of bile occurs in the intestine. During the postcibal period, dietary fat in the upper intestine stimulates gallbladder contraction in response to the enterohormone cholecystokinin. This step releases highly concentrated bile into the duodenum. Nutrients 2020, 12, 3709; doi:10.3390/nu12123709 www.mdpi.com/journal/nutrients Nutrients 2020, 12, 3709 2 of 30 In the intestine, BA promote the emulsification and absorption of dietary fat, i.e., cholesterol, triglycerides,Nutrients 2020, 12, x andFOR PEER fat-soluble REVIEW vitamins. Following ileal and colonic reabsorption,2 of BA 30 undergo continuous enterohepatic circulation several times daily. In the liver and intestine, BA suppress their owntriglycerides, synthesis, and and fat-soluble recent evidence vitamins. shows Follow thating BAileal are and potent colonic signalling reabsorption, molecules BA undergo with modulatory continuous enterohepatic circulation several times daily. In the liver and intestine, BA suppress their effects on epithelial cell proliferation, gene expression, fibrogenesis, as well as lipid and glucose own synthesis, and recent evidence shows that BA are potent signalling molecules with modulatory metabolism. Such effects are the consequence of BA acting as endogenous ligands and activation effects on epithelial cell proliferation, gene expression, fibrogenesis, as well as lipid and glucose ofmetabolism. the nuclear Such farnesoid effects are X the receptor consequence (FXR of or BA NR1H4), acting as the endogenous membrane-associated ligands and activation G-protein-coupled of bilethe nuclear acid receptor-1 farnesoid (GPBAR-1,X receptor (FXR also or known NR1H4) as, the transmembrane membrane-associated G protein-coupled G-protein-coupled receptor bile 5, TGR5), andacid receptor-1 sphingosine-1-phosphate (GPBAR-1, also known receptor as transmembrane 2 (S1PR2) in G the protein-coupled liver, intestine, receptor muscle 5, TGR5), and brown and adipose tissuesphingosine-1-phosphate [1–3]. Physiologically, receptor BA 2 are(S1PR2) confined in the almost liver, intestine, completely muscle within and brown the enterohepatic adipose tissue circulation, as[1–3]. only Physiologically, traces escape inBA the are general confined circulation. almost completely [4] Integrity within of the enterohepatic circulation, circulation as is therefore centralonly traces to biliaryescape homeostasis.in the general circulation. [4] Integrity of the enterohepatic circulation is therefore centralThis to biliary review homeostasis. will discuss in detail the complex pathways underlying BA homeostasis in physiology This review will discuss in detail the complex pathways underlying BA homeostasis in and during BA overload, their role as signalling molecules in particular for GPBAR-1. We also discuss physiology and during BA overload, their role as signalling molecules in particular for GPBAR-1. We thealso multiplediscuss the eff multipleects of this effects receptor of this onreceptor bile composition, on bile composition, cell lines, cell inflammation,lines, inflammation, gene-environment gene- interaction,environment togetherinteraction, with together potential with therapeuticpotential therapeutic approaches. approaches. 2. BA BA Synthesis, Synthesis, Secretion, Secretion, Biotransformation, Biotransformation, and Absorption and Absorption TheThe complex complex pathways pathways leading leading to BA to BAhomeostasis homeostasis in liver in liverand intestine and intestine [1,5,6] [are1,5 ,summarized6] are summarized in Figurein Figure1. 1. Figure 1. Cont. Nutrients 2020, 12, 3709 3 of 30 Nutrients 2020, 12, x FOR PEER REVIEW 3 of 30 Figure 1. (A) Sites of synthesis and metabolism of primary, secondary, and tertiary bile acids (BA) in humans. Cholesterol in the liver undergoes modification of the sterol ring, oxidation, and shortening of the side chain. The classical “neutral” pathway involves the cytochrome P450 enzyme, cholesterol Figure 1. (A) Sites of synthesis and metabolism of primary, secondary, and tertiary bile acids (BA) in 7α-hydroxylase (CYP7A1), and contributes to about 75–90% of total BA pool consisting of cholic acid humans. Cholesterol in the liver undergoes modification of the sterol ring, oxidation, and shortening (CA) and chenodeoxycholic acid (CDCA). The alternative “acidic” pathway is mitochondrial and of the side chain. The classical “neutral” pathway involves the cytochrome P450 enzyme, cholesterol contributes to 10–25% of total BA pool [1,7] with the rate-limiting enzyme cholesterol 27α-hydroxylase 7α-hydroxylase (CYP7A1), and contributes to about 75–90% of total BA pool consisting of cholic acid (CYP27A1) and then 25-hydroxycholesterol 7-alpha-hydroxylase (CYP7B1) [8,9] to produce CDCA. (CA) and chenodeoxycholic acid (CDCA). The alternative “acidic” pathway is mitochondrial and BA in the liver undergo conjugation with amino acids, glycine or taurine (ratio of 3:1), via N-acyl contributes to 10–25% of total BA pool [1,7] with the rate-limiting enzyme cholesterol 27α- amidation at carbon 24 of the aliphatic side chain [10] and active biliary secretion. In the colon the hydroxylase (CYP27A1) and then 25-hydroxycholesterol 7-alpha-hydroxylase (CYP7B1) [8,9] to resident bacteria interact with primary BA by dehydroxylation, dehydrogenation, 7α-dehydroxylation produce CDCA. BA in the liver undergo conjugation with amino acids, glycine or taurine (ratio of and epimerization. By this pathway, secondary BA are the dihydroxy deoxycholic acid (DCA) and 3:1), via N-acyl amidation at carbon 24 of the aliphatic side chain [10] and active biliary secretion. In the monohydroxy lithocholic acid (LCA). The 7α-dehydrogenation of CDCA forms the dihydroxy the colon the resident bacteria interact with primary BA by dehydroxylation, dehydrogenation, 7α- 7α-oxo-LCA which is metabolized to the “tertiary” 7β-epimer, the dihydroxy ursodeoxycholic acid (UDCA).dehydroxylation In the liver, and a smallepimerization. amount ofBy LCA this ispath quicklyway, secondary transformed BA to are sulphonated the dihydroxy form deoxycholic (S-LCA). Inacid the terminal(DCA) and ileum, the BAmonohydroxy uptake is about lithocholic 80% by acid active (LCA). transport The 7 withinα-dehydrogenation the enterocytes. of InCDCA the colon,
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