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      Metabolic effects of intestinal absorption and enterohepatic cycling of bile acids

      review-article
      a , b , a , *
      Acta Pharmaceutica Sinica. B
      Elsevier
      Bile acids, Liver, Intestine, Transporters, Lipid metabolism, Energy homeostasis, ACCII, acetyl-CoA carboxylase 2, APO, apolipoproteins, ASBT, apical sodium-dependent bile acid transporter, BSEP, bile salt export pump, CYP7A1, cholesterol 7α-hydroxylase, DIO2, deiodinase 2, FAS, fatty acid synthase, FGF, fibroblast growth factor, FOXO1, forkhead box protein O1, FGFR4, fibroblast growth factor receptor 4, FXR, farnesoid X-receptor, G6Pase, glucose-6-phosphatase, GLP-1, glucagon-like polypeptide-1, HNF4α, hepatocyte nuclear factor 4 alpha, IBABP, ileal bile acid binding protein, LDL, low density lipoprotein, NTCP, Na+-taurocholate transporting polypeptide, OATP, organic anion transporting polypeptide, OST, organic solute transporter, PEPCK, phosphoenolpyruvate carboxykinase, PGC1α, peroxisome proliferator-activated receptor gamma coactivator 1 alpha, PPAR, peroxisome proliferator-activated receptor, SHP, small heterodimer partner, SREBP1c, sterol regulatory element binding protein-1c, T4, thyroid hormone, TGR5, G-protein-coupled bile acid receptor, VLDL, very low density lipoprotein

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          Abstract

          The classical functions of bile acids include acting as detergents to facilitate the digestion and absorption of nutrients in the gut. In addition, bile acids also act as signaling molecules to regulate glucose homeostasis, lipid metabolism and energy expenditure. The signaling potential of bile acids in compartments such as the systemic circulation is regulated in part by an efficient enterohepatic circulation that functions to conserve and channel the pool of bile acids within the intestinal and hepatobiliary compartments. Changes in hepatobiliary and intestinal bile acid transport can alter the composition, size, and distribution of the bile acid pool. These alterations in turn can have significant effects on bile acid signaling and their downstream metabolic targets. This review discusses recent advances in our understanding of the inter-relationship between the enterohepatic cycling of bile acids and the metabolic consequences of signaling via bile acid-activated receptors, such as farnesoid X nuclear receptor (FXR) and the G-protein-coupled bile acid receptor (TGR5).

          Graphical abstract

          This review discusses recent advances in our understanding of the inter-relationship between the enterohepatic cycling of bile acids and the metabolic consequences of signaling via bile acid-activated receptors such as farnesoid X nuclear receptor (FXR) and the G-protein-coupled bile acid receptor (TGR5).

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          Most cited references52

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          Identification of a nuclear receptor for bile acids.

          Bile acids are essential for the solubilization and transport of dietary lipids and are the major products of cholesterol catabolism. Results presented here show that bile acids are physiological ligands for the farnesoid X receptor (FXR), an orphan nuclear receptor. When bound to bile acids, FXR repressed transcription of the gene encoding cholesterol 7alpha-hydroxylase, which is the rate-limiting enzyme in bile acid synthesis, and activated the gene encoding intestinal bile acid-binding protein, which is a candidate bile acid transporter. These results demonstrate a mechanism by which bile acids transcriptionally regulate their biosynthesis and enterohepatic transport.
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            Pleiotropic roles of bile acids in metabolism.

            Enzymatic oxidation of cholesterol generates numerous distinct bile acids that function both as detergents that facilitate digestion and absorption of dietary lipids, and as hormones that activate four distinct receptors. Activation of these receptors alters gene expression in multiple tissues, leading to changes not only in bile acid metabolism but also in glucose homeostasis, lipid and lipoprotein metabolism, energy expenditure, intestinal motility and bacterial growth, inflammation, liver regeneration, and hepatocarcinogenesis. This review covers the roles of specific bile acids, synthetic agonists, and their cognate receptors in controlling these diverse functions, as well as their current use in treating human diseases. Copyright © 2013 Elsevier Inc. All rights reserved.
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              Bile acids lower triglyceride levels via a pathway involving FXR, SHP, and SREBP-1c.

              We explored the effects of bile acids on triglyceride (TG) homeostasis using a combination of molecular, cellular, and animal models. Cholic acid (CA) prevents hepatic TG accumulation, VLDL secretion, and elevated serum TG in mouse models of hypertriglyceridemia. At the molecular level, CA decreases hepatic expression of SREBP-1c and its lipogenic target genes. Through the use of mouse mutants for the short heterodimer partner (SHP) and liver X receptor (LXR) alpha and beta, we demonstrate the critical dependence of the reduction of SREBP-1c expression by either natural or synthetic farnesoid X receptor (FXR) agonists on both SHP and LXR alpha and LXR beta. These results suggest that strategies aimed at increasing FXR activity and the repressive effects of SHP should be explored to correct hypertriglyceridemia.
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                Author and article information

                Contributors
                Journal
                Acta Pharm Sin B
                Acta Pharm Sin B
                Acta Pharmaceutica Sinica. B
                Elsevier
                2211-3835
                2211-3843
                20 February 2015
                March 2015
                20 February 2015
                : 5
                : 2
                : 129-134
                Affiliations
                [a ]Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Emory University, Atlanta, GA 30322, USA
                [b ]Molecular Medicine Graduate Program, Wake Forest School of Medicine, Winston-Salem, NC 27153, USA
                Author notes
                [* ]Corresponding author. Tel.: +1 404 7277083. paul.dawson@ 123456emory.edu
                Article
                S2211-3835(15)00003-9
                10.1016/j.apsb.2015.01.001
                4629214
                2073a42f-db7e-4041-b4aa-ebc3a92a360d
                © 2015 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 19 December 2014
                : 30 December 2014
                : 4 January 2015
                Categories
                Review

                bile acids,liver,intestine,transporters,lipid metabolism,energy homeostasis,accii, acetyl-coa carboxylase 2,apo, apolipoproteins,asbt, apical sodium-dependent bile acid transporter,bsep, bile salt export pump,cyp7a1, cholesterol 7α-hydroxylase,dio2, deiodinase 2,fas, fatty acid synthase,fgf, fibroblast growth factor,foxo1, forkhead box protein o1,fgfr4, fibroblast growth factor receptor 4,fxr, farnesoid x-receptor,g6pase, glucose-6-phosphatase,glp-1, glucagon-like polypeptide-1,hnf4α, hepatocyte nuclear factor 4 alpha,ibabp, ileal bile acid binding protein,ldl, low density lipoprotein,ntcp, na+-taurocholate transporting polypeptide,oatp, organic anion transporting polypeptide,ost, organic solute transporter,pepck, phosphoenolpyruvate carboxykinase,pgc1α, peroxisome proliferator-activated receptor gamma coactivator 1 alpha,ppar, peroxisome proliferator-activated receptor,shp, small heterodimer partner,srebp1c, sterol regulatory element binding protein-1c,t4, thyroid hormone,tgr5, g-protein-coupled bile acid receptor,vldl, very low density lipoprotein

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