Bile acids and their receptors in metabolic disorders. (April 2021)

• Record Type: Journal Article
• Authors: Fiorucci, Stefano; Distrutti, Eleonora; Carino, Adriana; Zampella, Angela; Biagioli, Michele
• Is Part Of: Progress in lipid research. Volume 82(2021)
• Publication Date: 2021-04
• Subjects: ABCA1 ATP-binding cassette transporter-1 -- ABCG5 ATP-binding cassette (ABC) transporters G5 -- ABCG8 ATP-binding cassette (ABC) transporters G8 -- AKT serine/threonine protein kinase PKB -- ApoA-I apolipoprotein A-I -- ApoC-II apolipoprotein C-II -- ApoC-III apolipoprotein C-III -- Apo A-IV apolipoprotein A-IV -- Apo A-V apolipoprotein A-V -- ApoE apolipoprotein E -- BSEP bile-salt export pump -- BAT brown adipose tissue -- CAR constitutive androstane receptor -- CE cholesterol ester -- CTE cytosolic Acyl-CoA thioesterase -- CHD coronary heart disease -- CEH cholesterolester hydrolase -- CPT1 Carnitine Palmitoyl Transferase 1 -- CYP7A1 cholesterol 7a-hydroxylase -- CYP8B1 sterol 12b-hydroxylase -- CYP3A4 Cytochrome P450 3A4 -- Cyp3a11 Cytochrome P450 3A11 -- D2 type II iodothyronine deionidase -- db/db diabetic mice -- Dio2 type II iodothyronine deiodinase gene -- ERK1/2 extracellular-regulated kinase 1 and 2 -- FBP1 fructose 1, 6bisphosphatate 1 -- FGF15 fibroblast growth factor 15 -- FGF19 fibroblast growth factor 19 -- FGFR4 fibroblast growth factor receptor4 -- Foxo1 forkhead box O1 transcriptional factor -- FXR farnesoid X receptor -- GLUT4 glucose transporter 4 -- G6Pase glucose-6-phosphatase -- HMG-CoA 3-hydroxymethyl-3-glutaryl coenzyme A -- HMGCoAS hydroxy-methylglutaryl CoA synthase -- HMGCoAR hydroxymethylglutaryl CoA reductase -- HNF4 hepatocyte nuclear factor 4 -- JNK Jun N-terminal Kinase -- LCAT lecithin-cholesterol acyl transferase -- LDL—c low density lipoprotein cholesterol -- L-PK L-pyruvate kinase -- LPL lipoprotein lipase -- LRH liver–relatedhomolog-1 -- Mdr Multi-Drug Resistance -- Mrp1 Mrp2 Mrp3 and Mrp4 Multidrug Resistance Associated Protein-1, 2, 3, 4 -- NTCP Na + taurocholate cotransport peptide -- Oatps organic anion transporting proteins -- ob/ob obese mice -- Osta/b organic solute transporter α and β -- PEPCK phosphoenolpyruvate carboxykinase -- PGC1a Peroxisome proliferator-activated receptor- coactivator (PGC)-1a -- PPARα peroxisome proliferator–activated receptor-α -- PPARγ peroxisome proliferator–activated receptor-γ -- PXR pregnane X receptor -- SCP sterol carrier protein -- SHP short heterodimer partner -- SRB1 scavenger receptor B1 -- SREBP1c sterol-regulatory-element-binding protein-1c -- SREBP2 Sterol regulatory element-binding protein 2 -- Sult2a1 sulfotransferase 2A1 -- TGR5 or M-BAR or GP-BAR1 or BG37 membrane bile acid receptor -- UCP-1-3 uncoupling protein 1–3 -- VDR vitamin D receptor; Lipids -- Periodicals; Lipids -- Periodicals; Lipides -- Périodiques; Lipiden; 572.57
• DOI: 10.1016/j.plipres.2021.101094
• Languages: English
• ISSNs: 0163-7827

Abstract

Abstract: Bile acids are a large family of atypical steroids which exert their functions by binding to a family of ubiquitous cell membrane and nuclear receptors. There are two main bile acid activated receptors, FXR and GPBAR1, that are exclusively activated by bile acids, while other receptors CAR, LXRs, PXR, RORγT, S1PR2and VDR are activated by bile acids in addition to other more selective endogenous ligands. In the intestine, activation of FXR and GPBAR1 promotes the release of FGF15/19 and GLP1 which integrate their signaling with direct effects exerted by theother receptors in target tissues. This network is tuned in a time ordered manner by circadian rhythm and is critical for the regulation of metabolic process including autophagy, fast-to-feed transition, lipid and glucose metabolism, energy balance and immune responses. In the last decade FXR ligands have entered clinical trials but development of systemic FXR agonists has been proven challenging because their side effects including increased levels of cholesterol and Low Density Lipoproteins cholesterol (LDL-c) and reduced High-Density Lipoprotein cholesterol (HDL-c). In addition, pruritus has emerged as a common, dose related, side effect of FXR ligands. Intestinal-restricted FXR and GPBAR1 agonists and dual FXR/GPBAR1 agonists have been developed. Here we review the last decade in bile acids physiology and pharmacology.