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Potential of Intestine-Selective FXR Modulation for Treatment of Metabolic Disease

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Bile Acids and Their Receptors

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 256))

Abstract

Farnesoid X receptor controls bile acid metabolism, both in the liver and intestine. This potent nuclear receptor not only maintains homeostasis of its own ligands, i.e., bile acids, but also regulates glucose and lipid metabolism as well as the immune system. These findings have led to substantial interest for FXR as a therapeutic target and to the recent approval of an FXR agonist for treating primary biliary cholangitis as well as ongoing clinical trials for other liver diseases. Given that FXR biology is complex, including moderate expression in tissues outside of the enterohepatic circulation, temporal expression of isoforms, posttranscriptional modifications, and the existence of several other bile acid-responsive receptors such as TGR5, clinical application of FXR modulators warrants thorough understanding of its actions. Recent findings have demonstrated remarkable physiological effects of targeting FXR specifically in the intestine (iFXR), thereby avoiding systemic release of modulators. These include local effects such as improvement of intestinal barrier function and intestinal cholesterol turnover, as well as systemic effects such as improvements in glucose homeostasis, insulin sensitivity, and nonalcoholic fatty liver disease (NAFLD). Intriguingly, metabolic improvements have been observed with both an iFXR agonist that leads to production of enteric Fgf15 and increased energy expenditure in adipose tissues and antagonists by reducing systemic ceramide levels and hepatic glucose production. Here we review the recent findings on the role of intestinal FXR and its targeting in metabolic disease.

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References

  • Abdelkarim M, Caron S, Duhem C et al (2010) The farnesoid X receptor regulates adipocyte differentiation and function by promoting peroxisome proliferator-activated receptor-gamma and interfering with the Wnt/beta-catenin pathways. J Biol Chem 285:36759–36767

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Abel U, Schlüter T, Schulz A et al (2010) Synthesis and pharmacological validation of a novel series of non-steroidal FXR agonists. Bioorg Med Chem Lett 20:4911–4917

    Article  CAS  PubMed  Google Scholar 

  • Ahrén B (2012) DPP-4 inhibition and islet function. J Diabetes Investig 3:3–10

    Article  PubMed  CAS  Google Scholar 

  • Albaugh VL, Banan B, Antoun J et al (2018) Role of bile acids and GLP-1 in mediating the metabolic improvements of bariatric surgery. Gastroenterology 156:1041–1051.e4

    Article  PubMed  CAS  Google Scholar 

  • Armstrong LE, Guo GL (2017) Role of FXR in liver inflammation during nonalcoholic steatohepatitis. Curr Pharmacol Rep 3:92–100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Attinkara R, Mwinyi J, Truninger K et al (2012) Association of genetic variation in the NR1H4 gene, encoding the nuclear bile acid receptor FXR, with inflammatory bowel disease. BMC Res Notes 5:461

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Balasubramaniyan N, Ananthanarayanan M, Suchy FJ (2012) Direct methylation of FXR by Set7/9, a lysine methyltransferase, regulates the expression of FXR target genes. Am J Physiol Gastrointest Liver Physiol 302:G937–G947

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Balasubramaniyan N, Luo Y, Sun AQ et al (2013) SUMOylation of the farnesoid X receptor (FXR) regulates the expression of FXR target genes. J Biol Chem 288:13850–13862

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Becares N, Gage MC, Pineda-Torra I (2017) Posttranslational modifications of lipid-activated nuclear receptors: focus on metabolism. Endocrinology 158:213–225

    Article  PubMed  CAS  Google Scholar 

  • Benhamed F, Filhoulaud G, Caron S et al (2015) O-GlcNAcylation links ChREBP and FXR to glucose-sensing. Front Endocrinol 5:230

    Article  Google Scholar 

  • Berge KE, Tian H, Graf GA et al (2000) Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters. Science 290:1771–1775

    Article  CAS  PubMed  Google Scholar 

  • Berrabah W, Aumercier P, Gheeraert C et al (2014) Glucose sensing O-GlcNAcylation pathway regulates the nuclear bile acid receptor farnesoid X receptor (FXR). Hepatology 59:2022–2033

    Article  CAS  PubMed  Google Scholar 

  • Bertolini A, van de Peppel IP, Doktorova-Demmin M et al (2019) Defective FXR-FGF15 signaling and bile acid homeostasis in cystic fibrosis mice can be restored by the laxative polyethylene glycol. Am J Physiol Gastrointest Liver Physiol 316:G404–G411

    Article  CAS  PubMed  Google Scholar 

  • Bilodeau S, Caron V, Gagnon J et al (2017) A CK2-RNF4 interplay coordinates non-canonical SUMOylation and degradation of nuclear receptor FXR. J Mol Cell Biol 9:195–208

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Binder HJ, Filburn B, Floch M (1975) Bile acid inhibition of intestinal anaerobic organisms. Am J Clin Nutr 28:119–125

    Article  CAS  PubMed  Google Scholar 

  • Boesjes M, Bloks VW, Hageman J et al (2014) Hepatic farnesoid X-receptor isoforms α2 and α4 differentially modulate bile salt and lipoprotein metabolism in mice. PLoS One 9:e115028

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Bonamassa B, Moschetta A (2013) Atherosclerosis: lessons from LXR and the intestine. Trends Endocrinol Metab 24:120–128

    Article  CAS  PubMed  Google Scholar 

  • Bonde Y, Eggertsen G, Rudling M (2016) Mice abundant in muricholic bile acids show resistance to dietary induced steatosis, weight gain, and to impaired glucose metabolism. PLoS One 11:e0147772

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Bosner MS, Lange LG, Stenson WF (1999) Percent cholesterol absorption in normal women and men quantified with dual stable isotopic tracers and negative ion mass spectrometry. J Lipid Res 40:302–308

    Article  CAS  PubMed  Google Scholar 

  • Brufau G, Stellaard F, Prado K et al (2010) Improved glycemic control with colesevelam treatment in patients with type 2 diabetes is not directly associated with changes in bile acid metabolism. Hepatology 52:1455–1464

    Article  CAS  PubMed  Google Scholar 

  • Bull LN, van Eijk MJ, Pawlikowska L et al (1998) A gene encoding a P-type ATPase mutated in two forms of hereditary cholestasis. Nat Genet 18:219–224

    Article  CAS  PubMed  Google Scholar 

  • Byun S, Kim YC, Zhang Y et al (2017) A postprandial FGF19-SHP-LSD1 regulatory axis mediates epigenetic repression of hepatic autophagy. EMBO J 36:1755–1769

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cariello M, Piccinin E, Garcia-Irigoyen O et al (2018) Nuclear receptor FXR, bile acids and liver damage: introducing the progressive familial intrahepatic cholestasis with FXR mutations. Biochim Biophys Acta Mol basis Dis 1864:1308–1318

    Article  CAS  PubMed  Google Scholar 

  • Cariou B, van Harmelen K, Duran-Sandoval D et al (2006) The farnesoid X receptor modulates adiposity and peripheral insulin sensitivity in mice. J Biol Chem 281:11039–11049

    Article  CAS  PubMed  Google Scholar 

  • Ceulemans LJ, Verbeke L, Decuypere J-P et al (2017) Farnesoid X receptor activation attenuates intestinal ischemia reperfusion injury in rats. PLoS One 12:e0169331

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Charach G, Argov O, Geiger K et al (2017) Diminished bile acids excretion is a risk factor for coronary artery disease: 20-year follow up and long-term outcome. Ther Adv Gastroenterol 4:1756283–7743420

    Google Scholar 

  • Chen L, McNulty J, Anderson D et al (2010) Cholestyramine reverses hyperglycemia and enhances glucose-stimulated glucagon-like peptide 1 release in Zucker diabetic fatty rats. J Pharmacol Exp Ther 334:164–170

    Article  CAS  PubMed  Google Scholar 

  • Chen L, Yao X, Young A et al (2012) Inhibition of apical sodium-dependent bile acid transporter as a novel treatment for diabetes. Am J Physiol Endocrinol Metab 302:68–76

    Article  CAS  Google Scholar 

  • Chen WG, Zheng JX, Xu X et al (2018) Hippocampal FXR plays a role in the pathogenesis of depression: a preliminary study based on lentiviral gene modulation. Psychiatry Res 264:374–379

    Article  PubMed  Google Scholar 

  • Cheng K, Metry M, Felton J et al (2018) Diminished gallbladder filling, increased fecal bile acids, and promotion of colon epithelial cell proliferation and neoplasia in fibroblast growth factor 15-deficient mice. Oncotarget 9:25572–25585

    Article  PubMed  PubMed Central  Google Scholar 

  • Choi M, Moschetta A, Bookout AL et al (2006) Identification of a hormonal basis for gallbladder filling. Nat Med 12:1253–1255

    Article  CAS  PubMed  Google Scholar 

  • Coleman OI, Lobner EM, Bierwirth S et al (2018) Activated ATF6 induces intestinal dysbiosis and innate immune response to promote colorectal tumorigenesis. Gastroenterology 155:1539–1552

    Article  CAS  PubMed  Google Scholar 

  • Cui G, Martin RC, Jin H et al (2018) Up-regulation of FGF15/19 signaling promotes hepatocellular carcinoma in the background of fatty liver. J Exp Clin Cancer Res 37:136

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Dawson PA (2017) Roles of Ileal ASBT and OSTα-OSTβ in regulating bile acid signaling. Dig Dis 35:261–266

    Article  PubMed  Google Scholar 

  • de Boer JF, Schonewille M, Boesjes M et al (2017) Intestinal farnesoid X receptor controls transintestinal cholesterol excretion in mice. Gastroenterology 152:1126–1138

    Article  PubMed  CAS  Google Scholar 

  • de Boer JF, Kuipers F, Groen AK (2018) Cholesterol transport revisited: a new turbo mechanism to drive cholesterol excretion. Trends Endocrinol Metab 29:123–133

    Article  PubMed  CAS  Google Scholar 

  • Degirolamo C, Rainaldi S, Bovenga F et al (2014) Microbiota modification with probiotics induces hepatic bile acid synthesis via downregulation of the Fxr-Fgf15 axis in mice. Cell Rep 7:12–18

    Article  CAS  PubMed  Google Scholar 

  • Degirolamo C, Modica S, Vacca M et al (2015) Prevention of spontaneous hepatocarcinogenesis in farnesoid X receptor-null mice by intestinal-specific farnesoid X receptor reactivation. Hepatology 61:161–170

    Article  CAS  PubMed  Google Scholar 

  • Ding JW, Andersson R, Soltesz V et al (1993) The role of bile and bile acids in bacterial translocation in obstructive jaundice in rats. Eur Surg Res 25:11–19

    Article  CAS  PubMed  Google Scholar 

  • Duran-Sandoval D, Mautino G, Martin G et al (2004) Glucose regulates the expression of the farnesoid X receptor in liver. Diabetes 53:890–898

    Article  CAS  PubMed  Google Scholar 

  • Fang Q, Li H, Song Q et al (2013) Serum fibroblast growth factor 19 levels are decreased in Chinese subjects with impaired fasting glucose and inversely associated with fasting plasma glucose levels. Diabetes Care 36:2810–2814

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fang S, Suh JM, Reilly SM et al (2015) Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance. Nat Med 21:159–165

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fedorowski T, Salen G, Tint GS et al (1979) Transformation of chenodeoxycholic acid and ursodeoxycholic acid by human intestinal bacteria. Gastroenterology 77:1068–1073

    Article  CAS  PubMed  Google Scholar 

  • Fei J, Fu L, Hu B et al (2019) Obeticholic acid alleviate lipopolysaccharide-induced acute lung injury via its anti-inflammatory effects in mice. Int Immunopharmacol 66:177–184

    Article  CAS  PubMed  Google Scholar 

  • Ferrebee CB, Li J, Haywood J et al (2018) Organic solute transporter α-β protects ileal enterocytes from bile acid-induced injury. Cell Mol Gastroenterol Hepatol 5:499–522

    Article  PubMed  PubMed Central  Google Scholar 

  • Frankenberg T, Miloh T, Chen FY et al (2008) The membrane protein ATPase class I type 8B member 1 signals through protein kinase C zeta to activate the farnesoid X receptor. Hepatology 48:1896–1905

    Article  CAS  PubMed  Google Scholar 

  • French DM, Lin BC, Wang M et al (2012) Targeting FGFR4 inhibits hepatocellular carcinoma in preclinical mouse models. PLoS One 7:e36713

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Friedman ES, Li Y, Shen TD et al (2018) FXR-dependent modulation of the human small intestinal microbiome by the bile acid derivative obeticholic acid. Gastroenterology 155:1741–1752

    Article  CAS  PubMed  Google Scholar 

  • Fu L, John LM, Adams SH et al (2004) Fibroblast growth factor 19 increases metabolic rate and reverses dietary and leptin-deficient diabetes. Endocrinology 145:2594–2603

    Article  CAS  PubMed  Google Scholar 

  • Fu S, Watkins SM, Hotamisligil GS (2012) The role of endoplasmic reticulum in hepatic lipid homeostasis and stress signaling. Cell Metab 15:623–634

    Article  CAS  PubMed  Google Scholar 

  • Fuchs CD, Traussnigg SA, Trauner M (2016) Nuclear receptor modulation for the treatment of nonalcoholic fatty liver disease. Semin Liver Dis 36:69–86

    Article  CAS  PubMed  Google Scholar 

  • Gadaleta RM, van Erpecum KJ, Oldenburg B et al (2011a) Farnesoid X receptor activation inhibits inflammation and preserves the intestinal barrier in inflammatory bowel disease. Gut 60:463–472

    Article  CAS  PubMed  Google Scholar 

  • Gadaleta RM, Oldenburg B, Willemsen ECL et al (2011b) Activation of bile salt nuclear receptor FXR is repressed by pro-inflammatory cytokines activating NF-κB signaling in the intestine. Biochim Biophys Acta Mol basis Dis 1812:851–858

    Article  CAS  Google Scholar 

  • Gai Z, Gui T, Hiller C et al (2016) Farnesoid X receptor protects against kidney injury in uninephrectomized obese mice. J Biol Chem 291:2397–2411

    Article  CAS  PubMed  Google Scholar 

  • Gineste G, Sirvent A, Paumelle R et al (2008) Phosphorylation of farnesoid X receptor by protein kinase C promotes its transcriptional activity. Mol Endocrinol 22:2433–2447

    Article  CAS  PubMed  Google Scholar 

  • Goodwin B, Jones SA, Price RR et al (2000) A regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis. Mol Cell 6:517–526

    Article  CAS  PubMed  Google Scholar 

  • Gray MA, Squires EJ (2015) Investigation of the dominant positive effect of porcine farnesoid X receptor (FXR) splice variant 1. Gene 560:71–76

    Article  CAS  PubMed  Google Scholar 

  • Han CY, Rho HS, Kim A et al (2018) FXR inhibits endoplasmic reticulum stress-induced NLRP3 inflammasome in hepatocytes and ameliorates liver injury. Cell Rep 24:2985–2999

    Article  CAS  PubMed  Google Scholar 

  • Handelsman Y (2011) Role of bile acid sequestrants in the treatment of type 2 diabetes. Diabetes Care 34:S244–S250

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Harrison SA, Rinella ME, Abdelmalek MF et al (2018) NGM282 for treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet 391:1174–1185

    Article  CAS  PubMed  Google Scholar 

  • Herman-Edelstein M, Weinstein T, Levi M (2018) Bile acid receptors and the kidney. Curr Opin Nephrol Hypertens 27:56–62

    Article  CAS  PubMed  Google Scholar 

  • Heuman DM (1989) Quantitative estimation of the hydrophilic-hydrophobic balance of mixed bile salt solutions. J Lipid Res 30:719–730

    Article  CAS  PubMed  Google Scholar 

  • Hill CJ, Lynch DB, Murphy K et al (2017) Evolution of gut microbiota composition from birth to 24 weeks in the INFANTMET cohort. Microbiome 5:4

    Article  PubMed  PubMed Central  Google Scholar 

  • Hofmann AF, Hagey LR (2014) Key discoveries in bile acid chemistry and biology and their clinical applications: history of the last eight decades. J Lipid Res 55:1553–1595

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huber RM, Murphy K, Miao B et al (2002) Generation of multiple farnesoid-X-receptor isoforms through the use of alternative promoters. Gene 290:35–43

    Article  CAS  PubMed  Google Scholar 

  • Inagaki T, Choi M, Moschetta A et al (2005) Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis. Cell Metab 2:217–225

    Article  CAS  PubMed  Google Scholar 

  • Inagaki T, Moschetta A, Lee Y-K et al (2006) Regulation of antibacterial defense in the small intestine by the nuclear bile acid receptor. Proc Natl Acad Sci 103:3920–3925

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jakulj L, van Dijk TH, de Boer JF et al (2016) Transintestinal cholesterol transport is active in mice and humans and controls ezetimibe-induced fecal neutral sterol excretion. Cell Metab 24:783–794

    Article  CAS  PubMed  Google Scholar 

  • Jiang C, Xie C, Li F et al (2015a) Intestinal farnesoid X receptor signaling promotes nonalcoholic fatty liver disease. J Clin Invest 125:386–402

    Article  PubMed  Google Scholar 

  • Jiang C, Xie C, Lv Y et al (2015b) Intestine-selective farnesoid X receptor inhibition improves obesity-related metabolic dysfunction. Nat Commun 6:10166

    Article  CAS  PubMed  Google Scholar 

  • Joyce SA, Gahan CGM (2016) Bile acid modifications at the microbe-host interface: potential for nutraceutical and pharmaceutical interventions in host health. Annu Rev Food Sci Technol 7:313–333

    Article  CAS  PubMed  Google Scholar 

  • Katafuchi T, Esterházy D, Lemoff A et al (2015) Detection of FGF15 in plasma by stable isotope standards and capture by anti-peptide antibodies and targeted mass spectrometry. Cell Metab 21:898–904

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kemper JK, Xiao Z, Ponugoti B et al (2009) FXR acetylation is normally dynamically regulated by p300 and SIRT1 but constitutively elevated in metabolic disease states. Cell Metab 10:392–404

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim H, Fang S (2018) Crosstalk between FXR and TGR5 controls glucagon-like peptide 1 secretion to maintain glycemic homeostasis. Lab Anim Res 34:140–146

    Article  PubMed  PubMed Central  Google Scholar 

  • Kim I, Ahn SH, Inagaki T et al (2007) Differential regulation of bile acid homeostasis by the farnesoid X receptor in liver and intestine. J Lipid Res 48:2664–2672

    Article  CAS  PubMed  Google Scholar 

  • Kim DH, Xiao Z, Kwon S et al (2014) A dysregulated acetyl/SUMO switch of FXR promotes hepatic inflammation in obesity. EMBO J 34:184–199

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Kim KH, Choi S, Zhou Y et al (2017) Hepatic FXR/SHP axis modulates systemic glucose and fatty acid homeostasis in aged mice. Hepatology 66:498–509

    Article  CAS  PubMed  Google Scholar 

  • Kim Y-C, Byun S, Seok S et al (2018) Small heterodimer partner and fibroblast growth factor 19 inhibit expression of NPC1L1 in mouse intestine and cholesterol absorption. Gastroenterology 156:1052–1065

    Article  PubMed  CAS  Google Scholar 

  • Kir S, Beddow SA, Samuel VT et al (2011) FGF19 as a postprandial, insulin-independent activator of hepatic protein and glycogen synthesis. Science 331:1621–1624

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kong B, Wang L, Chiang JYL et al (2012) Mechanism of tissue-specific farnesoid X receptor in suppressing the expression of genes in bile-acid synthesis in mice. Hepatology 56:1034–1043

    Article  CAS  PubMed  Google Scholar 

  • Kuipers F, Bloks VW, Groen AK (2014) Beyond intestinal soap – bile acids in metabolic control. Nat Rev Endocrinol 10:488–498

    Article  CAS  PubMed  Google Scholar 

  • Lan T, Morgan DA, Rahmouni K et al (2017) FGF19, FGF21, and an FGFR1/β-Klotho-activating antibody act on the nervous system to regulate body weight and glycemia. Cell Metab 26:709–718

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee J, Kemper JK (2010) Controlling SIRT1 expression by microRNAs in health and metabolic disease. Aging 2:527–534

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee J, Seok S, Yu P et al (2012) Genomic analysis of hepatic farnesoid X receptor binding sites reveals altered binding in obesity and direct gene repression by farnesoid X receptor in mice. Hepatology 56:108–117

    Article  CAS  PubMed  Google Scholar 

  • Lee JM, Wagner M, Xiao R et al (2014) Nutrient-sensing nuclear receptors coordinate autophagy. Nature 516:112–115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lefebvre P, Cariou B, Lien F et al (2009) Role of bile acids and bile acid receptors in metabolic regulation. Physiol Rev 89:147–191

    Article  CAS  PubMed  Google Scholar 

  • Li F, Jiang C, Krausz KW et al (2013) Microbiome remodelling leads to inhibition of intestinal farnesoid X receptor signalling and decreased obesity. Nat Commun 4:2384

    Article  PubMed  CAS  Google Scholar 

  • Lien F, Berthier A, Bouchaert E et al (2014) Metformin interferes with bile acid homeostasis through AMPK-FXR crosstalk. J Clin Invest 124:1037–1051

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu X, Guo GL, Kong B et al (2018) Farnesoid X receptor signaling activates the hepatic X-box binding protein 1 pathway in vitro and in mice. Hepatology 68:304–316

    Article  CAS  PubMed  Google Scholar 

  • Lu TT, Makishima M, Repa JJ et al (2000) Molecular basis for feedback regulation of bile acid synthesis by nuclear receptors. Mol Cell 6:507–515

    Article  CAS  PubMed  Google Scholar 

  • Luo L, Aubrecht J, Li D et al (2018) Assessment of serum bile acid profiles as biomarkers of liver injury and liver disease in humans. PLoS One 13:e0193824

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Makishima M, Okamoto AY, Repa JJ et al (1999) Identification of a nuclear receptor for bile acids. Science 284:1362–1365

    Article  CAS  PubMed  Google Scholar 

  • Maran RRM, Thomas A, Roth M et al (2009) Farnesoid X receptor deficiency in mice leads to increased intestinal epithelial cell proliferation and tumor development. J Pharmacol Exp Ther 328:469–477

    Article  CAS  PubMed  Google Scholar 

  • Maruyama T, Miyamoto Y, Nakamura T et al (2002) Identification of membrane-type receptor for bile acids (M-BAR). Biochem Biophys Res Commun 298:714–719

    Article  CAS  PubMed  Google Scholar 

  • Massafra V, Pellicciari R, Gioiello A et al (2018) Progress and challenges of selective farnesoid X receptor modulation. Pharmacol Ther 191:162–177

    Article  CAS  PubMed  Google Scholar 

  • Miura S, Mitsuhashi N, Shimizu H et al (2012) Fibroblast growth factor 19 expression correlates with tumor progression and poorer prognosis of hepatocellular carcinoma. BMC Cancer 12:56

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Modica S, Murzilli S, Salvatore L et al (2008) Nuclear bile acid receptor FXR protects against intestinal tumorigenesis. Cancer Res 68:9589–9594

    Article  CAS  PubMed  Google Scholar 

  • Modica S, Petruzzelli M, Bellafante E et al (2012) Selective activation of nuclear bile acid receptor FXR in the intestine protects mice against cholestasis. Gastroenterology 142:355–365

    Article  CAS  PubMed  Google Scholar 

  • Morton GJ, Matsen ME, Bracy DP et al (2013) FGF19 action in the brain induces insulin-independent glucose lowering. J Clin Invest 123:4799–4808

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mowat AM, Agace WW (2014) Regional specialization within the intestinal immune system. Nat Rev Immunol 14:667–685

    Article  CAS  PubMed  Google Scholar 

  • Mueller M, Thorell A, Claudel T et al (2015) Ursodeoxycholic acid exerts farnesoid X receptor-antagonistic effects on bile acid and lipid metabolism in morbid obesity. J Hepatol 62:1398–1404

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nakano T, Inoue I, Takenaka Y et al (2016) Ezetimibe promotes brush border membrane-to-lumen cholesterol efflux in the small intestine. PLoS One 11:e0152207

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Neuschwander-Tetri BA, Loomba R, Sanyal AJ et al (2015) Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet 385:956–965

    Article  CAS  PubMed  Google Scholar 

  • Nevens F, Andreone P, Mazzella G et al (2016) A placebo-controlled trial of obeticholic acid in primary biliary cholangitis. N Engl J Med 375:631–643

    Article  CAS  PubMed  Google Scholar 

  • Nicholes K, Guillet S, Tomlinson E et al (2002) A mouse model of hepatocellular carcinoma: ectopic expression of fibroblast growth factor 19 in skeletal muscle of transgenic mice. Am J Pathol 160:2295–2307

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nijmeijer RM, Gadaleta RM, van Mil SWC et al (2011) Farnesoid X receptor (FXR) activation and FXR genetic variation in inflammatory bowel disease. PLoS One 6:e23745

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Otte K, Kranz H, Kober I et al (2003) Identification of farnesoid X receptor beta as a novel mammalian nuclear receptor sensing lanosterol. Mol Cell Biol 23:864–872

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Out C, Patankar JV, Doktorova M et al (2015) Gut microbiota inhibit Asbt-dependent intestinal bile acid reabsorption via Gata4. J Hepatol 63:697–704

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Overington JP, Al-Lazikani B, Hopkins AL (2006) How many drug targets are there? Nat Rev Drug Discov 5:993–996

    Article  CAS  PubMed  Google Scholar 

  • Parks DJ, Blanchard SG, Bledsoe RK et al (1999) Bile acids: natural ligands for an orphan nuclear receptor. Science 284:1365–1368

    Article  CAS  PubMed  Google Scholar 

  • Parséus A, Sommer N, Sommer F et al (2017) Microbiota-induced obesity requires farnesoid X receptor. Gut 66:429–437

    Article  PubMed  CAS  Google Scholar 

  • Pathak P, Liu H, Boehme S et al (2017) Farnesoid X receptor induces Takeda G-protein receptor 5 cross-talk to regulate bile acid synthesis and hepatic metabolism. J Biol Chem 292:11055–11069

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pathak P, Xie C, Nichols RG et al (2018) Intestine farnesoid X receptor agonist and the gut microbiota activate G-protein bile acid receptor-1 signaling to improve metabolism. Hepatology 68:1574–1588

    Article  CAS  PubMed  Google Scholar 

  • Pencek R, Marmon T, Roth JD et al (2016) Effects of obeticholic acid on lipoprotein metabolism in healthy volunteers. Diabetes Obes Metab 18:936–940

    Article  CAS  PubMed  Google Scholar 

  • Potthoff MJ, Boney-Montoya J, Choi M et al (2011) FGF15/19 regulates hepatic glucose metabolism by inhibiting the CREB-PGC-1α pathway. Cell Metab 13:729–738

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rao A, Kosters A, Mells JE et al (2016) Inhibition of ileal bile acid uptake protects against nonalcoholic fatty liver disease in high-fat diet–fed mice. Sci Transl Med 8:357ra122–357ra357

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Raufman JP, Dawson PA, Rao A et al (2015) Slc10a2-null mice uncover colon cancer-promoting actions of endogenous fecal bile acids. Carcinogenesis 36:1193–1200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Renga B, Mencarelli A, Cipriani S et al (2013) The bile acid sensor FXR is required for immune-regulatory activities of TLR-9 in intestinal inflammation. PLoS One 8:e54472

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ryan KK, Tremaroli V, Clemmensen C et al (2014) FXR is a molecular target for the effects of vertical sleeve gastrectomy. Nature 509:183–188

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sayin SI, Wahlström A, Felin J et al (2013) Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist. Cell Metab 17:225–235

    Article  CAS  PubMed  Google Scholar 

  • Seok S, Fu T, Choi SE et al (2014) Transcriptional regulation of autophagy by an FXR-CREB axis. Nature 516:108–111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shapiro H, Kolodziejczyk AA, Halstuch D et al (2018) Bile acids in glucose metabolism in health and disease. J Exp Med 215:383–396

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sjöberg BG, Straniero S, Angelin B et al (2017) Cholestyramine treatment of healthy humans rapidly induces transient hypertriglyceridemia when treatment is initiated. Am J Physiol Endocrinol Metab 313:E167–E174

    Article  PubMed  Google Scholar 

  • Slijepcevic D, van de Graaf SFJ (2017) Bile acid uptake transporters as targets for therapy. Dig Dis 35:251–258

    Article  PubMed  Google Scholar 

  • Spinelli V, Lalloyer F, Baud G et al (2016) Influence of Roux-en-Y gastric bypass on plasma bile acid profiles: a comparative study between rats, pigs and humans. Int J Obes 40:1260–1267

    Article  CAS  Google Scholar 

  • Stahl GE, Mascarenhas MR, Fayer JC et al (1993) Passive jejunal bile salt absorption alters the enterohepatic circulation in immature rats. Gastroenterology 104:163–173

    Article  CAS  PubMed  Google Scholar 

  • Stenman LK, Holma R, Korpela R (2012) High-fat-induced intestinal permeability dysfunction associated with altered fecal bile acids. World J Gastroenterol 18:923–929

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stroeve JH, Brufau G, Stellaard F et al (2010) Intestinal FXR-mediated FGF15 production contributes to diurnal control of hepatic bile acid synthesis in mice. Lab Investig 90:1457–1467

    Article  CAS  PubMed  Google Scholar 

  • Suchy FJ, Balistreri WF, Heubi JE et al (1981) Physiologic cholestasis: elevation of the primary serum bile acid concentrations in normal infants. Gastroenterology 80:1037–1041

    Article  CAS  PubMed  Google Scholar 

  • Sun R, Yang N, Kong B et al (2017) Orally administered berberine modulates hepatic lipid metabolism by altering microbial bile acid metabolism and the intestinal FXR signaling pathway. Mol Pharmacol 91:110–122

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sun L, Xie C, Wang G et al (2018a) Gut microbiota and intestinal FXR mediate the clinical benefits of metformin. Nat Med 24:1919–1929

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sun L, Ma L, Ma Y et al (2018b) Insights into the role of gut microbiota in obesity: pathogenesis, mechanisms, and therapeutic perspectives. Protein Cell 9:397–403

    Article  PubMed  PubMed Central  Google Scholar 

  • Takahashi S, Fukami T, Masuo Y et al (2016) Cyp2c70 is responsible for the species difference in bile acid metabolism between mice and humans. J Lipid Res 57:2130–2137

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Teixeira TF, Souza NC, Chiarello PG et al (2012) Intestinal permeability parameters in obese patients are correlated with metabolic syndrome risk factors. Clin Nutr 31:735–740

    Article  CAS  PubMed  Google Scholar 

  • Temel RE, Brown JM (2015) A new model of reverse cholesterol transport: enTICEing strategies to stimulate intestinal cholesterol excretion. Trends Pharmacol Sci 36:440–451

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Thomas C, Gioiello A, Noriega L et al (2009) TGR5-mediated bile acid sensing controls glucose homeostasis. Cell Metab 10:167–177

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Thompson CA, Wojta K, Pulakanti K et al (2017) GATA4 is sufficient to establish jejunal versus ileal identity in the small intestine. Cell Mol Gastroenterol Hepatol 24:422–446

    Article  Google Scholar 

  • Thulesen J (2004) Glucagon-like peptide 2 (GLP-2), an intestinotrophic mediator. Curr Protein Pept Sci 5:51–65

    Article  CAS  PubMed  Google Scholar 

  • Toledo M, Batista-Gonzalez A, Merheb E et al (2018) Autophagy regulates the liver clock and glucose metabolism by degrading CRY1. Cell Metab 28:268–281

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tomlinson E, Fu L, John L et al (2002) Transgenic mice expressing human fibroblast growth factor-19 display increased metabolic rate and decreased adiposity. Endocrinology 143:1741–1747

    Article  CAS  PubMed  Google Scholar 

  • Trabelsi M-S, Daoudi M, Prawitt J et al (2015) Farnesoid X receptor inhibits glucagon-like peptide-1 production by enteroendocrine L cells. Nat Commun 6:7629

    Article  PubMed  Google Scholar 

  • Trauner M, Fuchs CD, Halilbasic E (2017) New therapeutic concepts in bile acid transport and signaling for management of cholestasis. Hepatology 65:1393–1404

    Article  PubMed  Google Scholar 

  • Uranga RM, Keller JN (2010) Diet and age interactions with regards to cholesterol regulation and brain pathogenesis. Curr Gerontol Geriatr Res 2010:219683

    Article  PubMed Central  CAS  Google Scholar 

  • van de Wiel SMW, de Waart DR, Oude Elferink RPJ et al (2018) Intestinal farnesoid X receptor activation by pharmacologic inhibition of the organic solute transporter α-β. Cell Mol Gastroenterol Hepatol 28:223–237

    Article  Google Scholar 

  • van Dijk TH, Grefhorst A, Oosterveer MH et al (2009) An increased flux through the glucose 6-phosphate pool in enterocytes delays glucose absorption in Fxr−/− mice. J Biol Chem 284:10315–10323

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • van Erpecum KJ, Schaap FG (2015) Intestinal failure to produce FGF19: a culprit in intestinal failure-associated liver disease? J Hepatol 62:1231–1233

    Article  PubMed  CAS  Google Scholar 

  • Vaquero J, Monte MJ, Dominguez M et al (2013) Differential activation of the human farnesoid X receptor depends on the pattern of expressed isoforms and the bile acid pool composition. Biochem Pharmacol 86:926–939

    Article  CAS  PubMed  Google Scholar 

  • Vavassori P, Mencarelli A, Renga B et al (2009) The bile acid receptor FXR is a modulator of intestinal innate immunity. J Immunol 183:6251–6261

    Article  CAS  PubMed  Google Scholar 

  • Verbeke L, Farre R, Verbinnen B et al (2015) The FXR agonist obeticholic acid prevents gut barrier dysfunction and bacterial translocation in cholestatic rats. Am J Pathol 185:409–419

    Article  CAS  PubMed  Google Scholar 

  • Verbeke L, Mannaerts I, Schierwagen R et al (2016) FXR agonist obeticholic acid reduces hepatic inflammation and fibrosis in a rat model of toxic cirrhosis. Sci Rep 16:33453

    Article  CAS  Google Scholar 

  • Verhulst PM, van der Velden LM, Oorschot V et al (2010) A flippase-independent function of ATP8B1, the protein affected in familial intrahepatic cholestasis type 1, is required for apical protein expression and microvillus formation in polarized epithelial cells. Hepatology 51:2049–2060

    Article  CAS  PubMed  Google Scholar 

  • Voshol PJ, Schwarz M, Rigotti A et al (2001) Down-regulation of intestinal scavenger receptor class B, type I (SR-BI) expression in rodents under conditions of deficient bile delivery to the intestine. Biochem J 356:317–325

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wagner SA, Beli P, Weinert BT et al (2012) Proteomic analyses reveal divergent ubiquitylation site patterns in murine tissues. Mol Cell Proteomics 11:1578–1585

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Walker EM, Thompson CA, Kohlnhofer BM et al (2014) Characterization of the developing small intestine in the absence of either GATA4 or GATA6. BMC Res Notes 11:902

    Article  CAS  Google Scholar 

  • Wang H, Chen J, Hollister K et al (1999) Endogenous bile acids are ligands for the nuclear receptor FXR/BAR. Mol Cell 3:543–553

    Article  CAS  PubMed  Google Scholar 

  • Wang Y-D, Chen W, Wang M et al (2008) Farnesoid X receptor antagonizes nuclear factor κB in hepatic inflammatory response. Hepatology 48:1632–1643

    Article  CAS  PubMed  Google Scholar 

  • Wang XX, Luo Y, Wang D et al (2017) A dual agonist of farnesoid X receptor (FXR) and the G protein-coupled receptor TGR5, INT-767, reverses age-related kidney disease in mice. J Biol Chem 292:12018–12024

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Watanabe M, Houten SM, Mataki C et al (2006) Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature 439:484–489

    Article  CAS  PubMed  Google Scholar 

  • Wheeler SG, Hammond CL, Jornayvaz FR et al (2014) Ostα−/− mice exhibit altered expression of intestinal lipid absorption genes, resistance to age-related weight gain, and modestly improved insulin sensitivity. Am J Physiol Gastrointest Liver Physiol 306:G425–G438

    Article  CAS  PubMed  Google Scholar 

  • Williams JA, Thomas AM, Li G et al (2012) Tissue specific induction of p62/Sqstm1 by farnesoid X receptor. PLoS One 7:e43961

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wu Y, Aquino CJ, Cowan DJ et al (2013) Discovery of a highly potent, nonabsorbable apical sodium-dependent bile acid transporter inhibitor (GSK2330672) for treatment of type 2 diabetes. J Med Chem 56:5094–5114

    Article  CAS  PubMed  Google Scholar 

  • Xie C, Jiang C, Shi J et al (2017) An intestinal farnesoid X receptor-ceramide signaling axis modulates hepatic gluconeogenesis in mice. Diabetes 66:613–626

    Article  CAS  PubMed  Google Scholar 

  • Xiong X, Wang X, Lu Y et al (2014) Hepatic steatosis exacerbated by endoplasmic reticulum stress-mediated downregulation of FXR in aging mice. J Hepatol 60:847–854

    Article  CAS  PubMed  Google Scholar 

  • Zhang Y, Kast-Woelbern HR, Edwards PA (2003) Natural structural variants of the nuclear receptor farnesoid X receptor affect transcriptional activation. J Biol Chem 278:104–110

    Article  CAS  PubMed  Google Scholar 

  • Zhang Y, Castellani LW, Sinal CJ et al (2004) Peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) regulates triglyceride metabolism by activation of the nuclear receptor FXR. Genes Dev 18:157–169

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang Y, Edwards PA (2008) FXR signaling in metabolic disease. FEBS Lett 582:10–18

    Article  CAS  PubMed  Google Scholar 

  • Zhang L, Xie C, Nichols RG et al (2016) Farnesoid X receptor signaling shapes the gut microbiota and controls hepatic lipid metabolism. mSystems 1:e00070–e00016

    Article  PubMed  PubMed Central  Google Scholar 

  • Zhou M, Luo J, Chen M et al (2017) Mouse species-specific control of hepatocarcinogenesis and metabolism by FGF19/FGF15. J Hepatol 66:1182–1192

    Article  CAS  PubMed  Google Scholar 

  • Zimmermann P, Hirsch-Hoffmann M, Hennig L et al (2004) GENEVESTIGATOR. Arabidopsis microarray database and analysis toolbox. Plant Physiol 136:2621–2632

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Pediatrics, University Medical Center Groningen, Faculty Campus Fryslân, University of Groningen, Groningen, The Netherlands

    Tim van Zutphen, Anna Bertolini, Hilde D. de Vries, Vincent W. Bloks, Jan Freark de Boer, Johan W. Jonker & Folkert Kuipers

  2. University of Groningen, Leeuwarden, The Netherlands

    Tim van Zutphen & Hilde D. de Vries

  3. Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

    Jan Freark de Boer & Folkert Kuipers

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  1. Tim van Zutphen
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  2. Anna Bertolini
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Correspondence to Folkert Kuipers .

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  1. University of Perugia, School of Medicine, Perugia, Italy

    Stefano Fiorucci

  2. S.C. Gastroenterologia, Azienda Ospedaliera di Perugia, Perugia, Italy

    Eleonora Distrutti

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van Zutphen, T. et al. (2019). Potential of Intestine-Selective FXR Modulation for Treatment of Metabolic Disease. In: Fiorucci, S., Distrutti, E. (eds) Bile Acids and Their Receptors. Handbook of Experimental Pharmacology, vol 256. Springer, Cham. https://doi.org/10.1007/164_2019_233

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