Diabetes Metab J.  2019 Jun;43(3):257-272. 10.4093/dmj.2019.0043.

Understanding Bile Acid Signaling in Diabetes: From Pathophysiology to Therapeutic Targets

Affiliations
  • 1Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH, USA. jchiang@neomed.edu

Abstract

Diabetes and obesity have reached an epidemic status worldwide. Diabetes increases the risk for cardiovascular disease and non-alcoholic fatty liver disease. Primary bile acids are synthesized in hepatocytes and are transformed to secondary bile acids in the intestine by gut bacteria. Bile acids are nutrient sensors and metabolic integrators that regulate lipid, glucose, and energy homeostasis by activating nuclear farnesoid X receptor and membrane Takeda G protein-coupled receptor 5. Bile acids control gut bacteria overgrowth, species population, and protect the integrity of the intestinal barrier. Gut bacteria, in turn, control circulating bile acid composition and pool size. Dysregulation of bile acid homeostasis and dysbiosis causes diabetes and obesity. Targeting bile acid signaling and the gut microbiome have therapeutic potential for treating diabetes, obesity, and non-alcoholic fatty liver disease.

Keyword

Bile acids and salts; Gastrointestinal microbiome; Non-alcoholic fatty liver disease; Receptors, cytoplasmic and nuclear; Receptors, G-protein-coupled

MeSH Terms

Bacteria
Bile Acids and Salts
Bile*
Cardiovascular Diseases
Dysbiosis
Gastrointestinal Microbiome
Glucose
Hepatocytes
Homeostasis
Intestines
Membranes
Non-alcoholic Fatty Liver Disease
Obesity
Receptors, Cytoplasmic and Nuclear
Receptors, G-Protein-Coupled
Bile Acids and Salts
Glucose
Receptors, Cytoplasmic and Nuclear
Receptors, G-Protein-Coupled

Figure

  • Fig. 1 Metabolic syndrome is a collection of five phenotypes: hypertension, hyperglycemia, hypertriglyceridemia, insulin resistance and obesity. Many of these metabolic phenotypes are associated with type 2 diabetes mellitus (T2DM). T2DM increases risk for cardiovascular disease (CVD) and non-alcoholic fatty liver disease (NAFLD). NAFLD is a spectrum of liver disease including simple steatosis, nonalcoholic steatohepatitis (NASH), liver fibrosis, cirrhosis, and hepatocellular carcinoma. Obesity, hepatic steatosis and insulin resistance all contribute to NAFLD.

  • Fig. 2 Bile acid synthesis, enterohepatic circulation of bile acids, and bile acid transport. In human hepatocytes, cholesterol 7α-hydroxylase (CYP7A1) catalyzes the first and rate-limiting step in the classic pathway of bile acid synthesis in which cholic acid (CA) and chenodeoxycholic acid (CDCA) are synthesized from cholesterol. Sterol 12α-hydroxylase (CYP8B1) is required for synthesis of CA, and without this enzyme CDCA is synthesized. The alternative pathway is initiated by sterol 27-hydroxylase (CYP27A1), which catalyzes steroid side-chain oxidation, followed by oxysterol 7α-hydroxylase (CYP7B1), which synthesizes the oxidized sterols that form CA and CDCA in hepatocytes. CYP7A1 is liver-specific, while CYP27A1 and CYP7B1 are expressed in extrahepatic tissues and macrophages. Bile acids are conjugated to the amino acids taurine (T) or glycine (G) for secretion into bile via bile salt export pump (BSEP). Bile acids are reabsorbed in the ileum via apical sodium-dependent bile acid transporter (ASBT) in enterocytes, where gut bacterial bile salt hydrolase (BSH) de-conjugates bile acids and 7α-dehydroxylase removes a hydroxyl group to form the secondary bile acids, deoxycholic acid (DCA) and lithocholic acid (LCA) from CA and CDCA, respectively. Bile acids are effluxed to portal blood via organic solute transporter α and β (OSTα/OSTβ) dimers and are transported to hepatocytes via Na2+-dependent taurocholate co-transporting peptide (NTCP) where they inhibit bile acid synthesis. Bile acids activate hepatic farnesoid X receptor (FXR) to induce small heterodimer partner (SHP), which inhibits CYP7A1 and CYP8B1 gene transcription. In enterocytes, bile acid activation of FXR induces fibroblast growth factor 19 (FGF19). FGF19 is transported to hepatocytes to activate FGF receptor 4 (FGFR4)/β-Klotho complex, which activates EKR1/2 signaling to inhibit CYP7A1 gene transcription. Bile acids activate Takeda G protein-coupled receptor 5 (TGR5) in intestinal L-cells, leading to secretion of glucagon-like peptide-1 (GLP-1), which stimulates insulin secretion from β-cells. In adipose tissue, activation of TGR5 stimulates cAMP/cAMP response element binding protein (CREBP) to induce thyroid hormone deiodinase type 2 (DIO2), which converts thyroxine (T4) to triiodothyronine (T3) and stimulates energy metabolism. ERK1/2, extracellular regulated kinase 1 and 2; PPARα, peroxisome proliferator-activated receptor α; GCA, glycocholic acid; GCDCA, glycochenodeoxycholic acid; TCA, taurocholic acid; TCDCA, taurochenodeoxycholic acid.

  • Fig. 3 Nutrient regulation of bile acid synthesis, insulin signaling, and mechanistic target of rapamycin complex 1 (mTORC1) signaling. Feeding induces cholesterol 7α-hydroxylase (CYP7A1) but inhibits sterol 12α-hydroxylase (CYP8B1), while fasting inhibits CYP7A1 but induces CYP8B1. Feeding and fasting cycles affect bile acid synthesis and composition, which in turn regulate hepatic lipid and glucose metabolism. After feeding and during the postprandial state, bile acids are released from the gallbladder to aid in nutrient absorption. In hepatocytes, CYP7A1 and bile acid synthesis are stimulated to activate farnesoid X receptor (FXR) signaling and insulin/insulin receptor substrate 1 (IRS1)-AKT-phosphoinositide 3-kinase (PI3K) signaling. Insulin signaling inhibits mTORC1/protein S6 kinase (S6K) signaling and steroid regulatory element binding protein 1c (SREBP1c)-mediated lipogenesis. During the late post-prandial state, FXR induces fibroblast growth factor 19 (FGF19) to inhibit CYP7A1 and bile acid synthesis via FGF receptor 4 (FGFR4)/β-Klotho/extracellular regulated kinase 1 and 2 (ERK1/2) signaling. During fasting and prolonged starvation, free fatty acids released from adipose triglycerides activate peroxisome proliferator-activated receptor γ (PPARγ) in adipose tissue and PPARα in hepatocytes, and induce FGF21. FGF21 induces peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) to stimulate mitochondrial oxidative phosphorylation and energy production. FGF21 also inhibits mTORC1 signaling to stimulate insulin signaling. In enterocytes, FXR induces ceramides, which activate mTORC1/S6K signaling and stimulate processing of full length SREBP1c to its nuclear form (nSREBP1), stimulating lipogenesis. During fasting, CYP8B1 is induced and increases synthesis of cholic acid (CA) and deoxycholic acid (DCA). DCA activates intestinal FXR and ceramide synthesis. CYP8B1 inhibits FGF21 and activates mTORC1 signaling via inhibition of PPARα. CDCA, chenodeoxycholic acid; TCA, taurocholic acid; TGR5, Takeda G protein-coupled receptor 5; CREBP, cAMP response element binding protein; DIO2, deiodinase type 2; T, taurine; TCDCA, taurochenodeoxycholic acid; LCA, lithocholic acid; DCA, deoxycholic acid.


Cited by  1 articles

Diabetes and Metabolism Journal in 2020: Good to Great
In-Kyung Jeong
Diabetes Metab J. 2020;44(1):1-2.    doi: 10.4093/dmj.2020.0032.


Reference

1. Rowley WR, Bezold C, Arikan Y, Byrne E, Krohe S. Diabetes 2030: insights from yesterday, today, and future trends. Popul Health Manag. 2017; 20:6–12.
2. Finkelstein EA, Khavjou OA, Thompson H, Trogdon JG, Pan L, Sherry B, Dietz W. Obesity and severe obesity forecasts through 2030. Am J Prev Med. 2012; 42:563–570.
3. Targher G, Marchesini G, Byrne CD. Risk of type 2 diabetes in patients with non-alcoholic fatty liver disease: causal association or epiphenomenon? Diabetes Metab. 2016; 42:142–156.
4. Younossi Z, Anstee QM, Marietti M, Hardy T, Henry L, Eslam M, George J, Bugianesi E. Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol. 2018; 15:11–20.
5. Lonardo A, Nascimbeni F, Mantovani A, Targher G. Hypertension, diabetes, atherosclerosis and NASH: cause or consequence? J Hepatol. 2018; 68:335–352.
6. Targher G, Byrne CD, Lonardo A, Zoppini G, Barbui C. Non-alcoholic fatty liver disease and risk of incident cardiovascular disease: a meta-analysis. J Hepatol. 2016; 65:589–600.
7. Ma J, Hwang SJ, Pedley A, Massaro JM, Hoffmann U, Chung RT, Benjamin EJ, Levy D, Fox CS, Long MT. Bi-directional analysis between fatty liver and cardiovascular disease risk factors. J Hepatol. 2017; 66:390–397.
8. Chimakurthi CR, Rowe IA. Establishing the independence and clinical importance of non-alcoholic fatty liver disease as a risk factor for cardiovascular disease. J Hepatol. 2016; 65:1265–1266.
9. den Boer M, Voshol PJ, Kuipers F, Havekes LM, Romijn JA. Hepatic steatosis: a mediator of the metabolic syndrome. Lessons from animal models. Arterioscler Thromb Vasc Biol. 2004; 24:644–649.
10. Ginsberg HN, Zhang YL, Hernandez-Ono A. Metabolic syndrome: focus on dyslipidemia. Obesity (Silver Spring). 2006; 14:Suppl 1. 41S–49S.
11. Brunt EM. Pathology of nonalcoholic fatty liver disease. Nat Rev Gastroenterol Hepatol. 2010; 7:195–203.
12. Machado MV, Diehl AM. Pathogenesis of nonalcoholic steatohepatitis. Gastroenterology. 2016; 150:1769–1777.
13. Hardy T, Oakley F, Anstee QM, Day CP. Nonalcoholic fatty liver disease: pathogenesis and disease spectrum. Annu Rev Pathol. 2016; 11:451–496.
14. Haas JT, Francque S, Staels B. Pathophysiology and mechanisms of nonalcoholic fatty liver disease. Annu Rev Physiol. 2016; 78:181–205.
15. Farrell GC, Larter CZ. Nonalcoholic fatty liver disease: from steatosis to cirrhosis. Hepatology. 2006; 43:2 Suppl 1. S99–S112.
16. Chiang JY. Bile acids: regulation of synthesis. J Lipid Res. 2009; 50:1955–1966.
17. Prawitt J, Caron S, Staels B. Bile acid metabolism and the pathogenesis of type 2 diabetes. Curr Diab Rep. 2011; 11:160–166.
18. Haeusler RA, Astiarraga B, Camastra S, Accili D, Ferrannini E. Human insulin resistance is associated with increased plasma levels of 12α-hydroxylated bile acids. Diabetes. 2013; 62:4184–4191.
19. Haeusler RA, Pratt-Hyatt M, Welch CL, Klaassen CD, Accili D. Impaired generation of 12-hydroxylated bile acids links hepatic insulin signaling with dyslipidemia. Cell Metab. 2012; 15:65–74.
20. Chiang JYL, Ferrell JM. Bile acid metabolism in liver pathobiology. Gene Expr. 2018; 18:71–87.
21. Chiang JYL. Bile acid metabolism and signaling in liver disease and therapy. Liver Res. 2017; 1:3–9.
22. Wang H, Chen J, Hollister K, Sowers LC, Forman BM. Endogenous bile acids are ligands for the nuclear receptor FXR/BAR. Mol Cell. 1999; 3:543–553.
23. Makishima M, Okamoto AY, Repa JJ, Tu H, Learned RM, Luk A, Hull MV, Lustig KD, Mangelsdorf DJ, Shan B. Identification of a nuclear receptor for bile acids. Science. 1999; 284:1362–1365.
24. Parks DJ, Blanchard SG, Bledsoe RK, Chandra G, Consler TG, Kliewer SA, Stimmel JB, Willson TM, Zavacki AM, Moore DD, Lehmann JM. Bile acids: natural ligands for an orphan nuclear receptor. Science. 1999; 284:1365–1368.
25. Makishima M, Lu TT, Xie W, Whitfield GK, Domoto H, Evans RM, Haussler MR, Mangelsdorf DJ. Vitamin D receptor as an intestinal bile acid sensor. Science. 2002; 296:1313–1316.
26. Goodwin B, Gauthier KC, Umetani M, Watson MA, Lochansky MI, Collins JL, Leitersdorf E, Mangelsdorf DJ, Kliewer SA, Repa JJ. Identification of bile acid precursors as endogenous ligands for the nuclear xenobiotic pregnane X receptor. Proc Natl Acad Sci U S A. 2003; 100:223–228.
27. Maruyama T, Miyamoto Y, Nakamura T, Tamai Y, Okada H, Sugiyama E, Nakamura T, Itadani H, Tanaka K. Identification of membrane-type receptor for bile acids (M-BAR). Biochem Biophys Res Commun. 2002; 298:714–719.
28. Studer E, Zhou X, Zhao R, Wang Y, Takabe K, Nagahashi M, Pandak WM, Dent P, Spiegel S, Shi R, Xu W, Liu X, Bohdan P, Zhang L, Zhou H, Hylemon PB. Conjugated bile acids activate the sphingosine-1-phosphate receptor 2 in primary rodent hepatocytes. Hepatology. 2012; 55:267–276.
29. Raufman JP, Cheng K, Zimniak P. Activation of muscarinic receptor signaling by bile acids: physiological and medical implications. Dig Dis Sci. 2003; 48:1431–1444.
30. Lefebvre P, Cariou B, Lien F, Kuipers F, Staels B. Role of bile acids and bile acid receptors in metabolic regulation. Physiol Rev. 2009; 89:147–191.
31. Sinal CJ, Tohkin M, Miyata M, Ward JM, Lambert G, Gonzalez FJ. Targeted disruption of the nuclear receptor FXR/BAR impairs bile acid and lipid homeostasis. Cell. 2000; 102:731–744.
32. Li T, Chiang JY. Bile acid signaling in metabolic disease and drug therapy. Pharmacol Rev. 2014; 66:948–983.
33. Duran-Sandoval D, Mautino G, Martin G, Percevault F, Barbier O, Fruchart JC, Kuipers F, Staels B. Glucose regulates the expression of the farnesoid X receptor in liver. Diabetes. 2004; 53:890–898.
34. Ma K, Saha PK, Chan L, Moore DD. Farnesoid X receptor is essential for normal glucose homeostasis. J Clin Invest. 2006; 116:1102–1109.
35. Cariou B, van Harmelen K, Duran-Sandoval D, van Dijk TH, Grefhorst A, Abdelkarim M, Caron S, Torpier G, Fruchart JC, Gonzalez FJ, Kuipers F, Staels B. The farnesoid X receptor modulates adiposity and peripheral insulin sensitivity in mice. J Biol Chem. 2006; 281:11039–11049.
36. Zhang Y, Lee FY, Barrera G, Lee H, Vales C, Gonzalez FJ, Willson TM, Edwards PA. Activation of the nuclear receptor FXR improves hyperglycemia and hyperlipidemia in diabetic mice. Proc Natl Acad Sci U S A. 2006; 103:1006–1011.
37. Watanabe M, Horai Y, Houten SM, Morimoto K, Sugizaki T, Arita E, Mataki C, Sato H, Tanigawara Y, Schoonjans K, Itoh H, Auwerx J. Lowering bile acid pool size with a synthetic farnesoid X receptor (FXR) agonist induces obesity and diabetes through reduced energy expenditure. J Biol Chem. 2011; 286:26913–26920.
38. Dufer M, Horth K, Wagner R, Schittenhelm B, Prowald S, Wagner TF, Oberwinkler J, Lukowski R, Gonzalez FJ, Krippeit-Drews P, Drews G. Bile acids acutely stimulate insulin secretion of mouse β-cells via farnesoid X receptor activation and K(ATP) channel inhibition. Diabetes. 2012; 61:1479–1489.
39. Keitel V, Reinehr R, Gatsios P, Rupprecht C, Gorg B, Selbach O, Haussinger D, Kubitz R. The G-protein coupled bile salt receptor TGR5 is expressed in liver sinusoidal endothelial cells. Hepatology. 2007; 45:695–704.
40. Keitel V, Ullmer C, Haussinger D. The membrane-bound bile acid receptor TGR5 (Gpbar-1) is localized in the primary cilium of cholangiocytes. Biol Chem. 2010; 391:785–789.
41. Keitel V, Haussinger D. Role of TGR5 (GPBAR1) in liver disease. Semin Liver Dis. 2018; 38:333–339.
42. Keitel V, Cupisti K, Ullmer C, Knoefel WT, Kubitz R, Haussinger D. The membrane-bound bile acid receptor TGR5 is localized in the epithelium of human gallbladders. Hepatology. 2009; 50:861–870.
43. Donepudi AC, Boehme S, Li F, Chiang JY. G-protein-coupled bile acid receptor plays a key role in bile acid metabolism and fasting-induced hepatic steatosis in mice. Hepatology. 2017; 65:813–827.
44. Alemi F, Poole DP, Chiu J, Schoonjans K, Cattaruzza F, Grider JR, Bunnett NW, Corvera CU. The receptor TGR5 mediates the prokinetic actions of intestinal bile acids and is required for normal defecation in mice. Gastroenterology. 2013; 144:145–154.
45. Keitel V, Donner M, Winandy S, Kubitz R, Haussinger D. Expression and function of the bile acid receptor TGR5 in Kupffer cells. Biochem Biophys Res Commun. 2008; 372:78–84.
46. Thomas C, Gioiello A, Noriega L, Strehle A, Oury J, Rizzo G, Macchiarulo A, Yamamoto H, Mataki C, Pruzanski M, Pellicciari R, Auwerx J, Schoonjans K. TGR5-mediated bile acid sensing controls glucose homeostasis. Cell Metab. 2009; 10:167–177.
47. Broeders EP, Nascimento EB, Havekes B, Brans B, Roumans KH, Tailleux A, Schaart G, Kouach M, Charton J, Deprez B, Bouvy ND, Mottaghy F, Staels B, van Marken Lichtenbelt WD, Schrauwen P. The bile acid chenodeoxycholic acid increases human brown adipose tissue activity. Cell Metab. 2015; 22:418–426.
48. Vassileva G, Golovko A, Markowitz L, Abbondanzo SJ, Zeng M, Yang S, Hoos L, Tetzloff G, Levitan D, Murgolo NJ, Keane K, Davis HR Jr, Hedrick J, Gustafson EL. Targeted deletion of Gpbar1 protects mice from cholesterol gallstone formation. Biochem J. 2006; 398:423–430.
49. Vassileva G, Hu W, Hoos L, Tetzloff G, Yang S, Liu L, Kang L, Davis HR, Hedrick JA, Lan H, Kowalski T, Gustafson EL. Gender-dependent effect of Gpbar1 genetic deletion on the metabolic profiles of diet-induced obese mice. J Endocrinol. 2010; 205:225–232.
50. Pathak P, Liu H, Boehme S, Xie C, Krausz KW, Gonzalez F, Chiang JYL. Farnesoid X receptor induces Takeda G-protein receptor 5 cross-talk to regulate bile acid synthesis and hepatic metabolism. J Biol Chem. 2017; 292:11055–11069.
51. Pathak P, Li T, Chiang JY. Retinoic acid-related orphan receptor α regulates diurnal rhythm and fasting induction of sterol 12α-hydroxylase in bile acid synthesis. J Biol Chem. 2013; 288:37154–37165.
52. Ferrell JM, Chiang JY. Circadian rhythms in liver metabolism and disease. Acta Pharm Sin B. 2015; 5:113–122.
53. Ferrell JM, Chiang JY. Short-term circadian disruption impairs bile acid and lipid homeostasis in mice. Cell Mol Gastroenterol Hepatol. 2015; 1:664–677.
54. Donepudi AC, Ferrell JM, Boehme S, Choi HS, Chiang JYL. Deficiency of cholesterol 7α-hydroxylase in bile acid synthesis exacerbates alcohol-induced liver injury in mice. Hepatol Commun. 2017; 2:99–112.
55. Seok S, Fu T, Choi SE, Li Y, Zhu R, Kumar S, Sun X, Yoon G, Kang Y, Zhong W, Ma J, Kemper B, Kemper JK. Transcriptional regulation of autophagy by an FXR-CREB axis. Nature. 2014; 516:108–111.
56. Wang Y, Ding Y, Li J, Chavan H, Matye D, Ni HM, Chiang JY, Krishnamurthy P, Ding WX, Li T. Targeting the enterohepatic bile acid signaling induces hepatic autophagy via a CYP7A1-AKT-mTOR axis in mice. Cell Mol Gastroenterol Hepatol. 2016; 3:245–260.
57. Owen JL, Zhang Y, Bae SH, Farooqi MS, Liang G, Hammer RE, Goldstein JL, Brown MS. Insulin stimulation of SREBP-1c processing in transgenic rat hepatocytes requires p70 S6-kinase. Proc Natl Acad Sci U S A. 2012; 109:16184–16189.
58. Inagaki T, Choi M, Moschetta A, Peng L, Cummins CL, McDonald JG, Luo G, Jones SA, Goodwin B, Richardson JA, Gerard RD, Repa JJ, Mangelsdorf DJ, Kliewer SA. Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis. Cell Metab. 2005; 2:217–225.
59. Song KH, Li T, Owsley E, Strom S, Chiang JY. Bile acids activate fibroblast growth factor 19 signaling in human hepatocytes to inhibit cholesterol 7alpha-hydroxylase gene expression. Hepatology. 2009; 49:297–305.
60. Schlein C, Talukdar S, Heine M, Fischer AW, Krott LM, Nilsson SK, Brenner MB, Heeren J, Scheja L. FGF21 lowers plasma triglycerides by accelerating lipoprotein catabolism in white and brown adipose tissues. Cell Metab. 2016; 23:441–453.
61. Galman C, Lundasen T, Kharitonenkov A, Bina HA, Eriksson M, Hafstrom I, Dahlin M, Amark P, Angelin B, Rudling M. The circulating metabolic regulator FGF21 is induced by prolonged fasting and PPARalpha activation in man. Cell Metab. 2008; 8:169–174.
62. Potthoff MJ, Inagaki T, Satapati S, Ding X, He T, Goetz R, Mohammadi M, Finck BN, Mangelsdorf DJ, Kliewer SA, Burgess SC. FGF21 induces PGC-1alpha and regulates carbohydrate and fatty acid metabolism during the adaptive starvation response. Proc Natl Acad Sci U S A. 2009; 106:10853–10858.
63. Xu J, Lloyd DJ, Hale C, Stanislaus S, Chen M, Sivits G, Vonderfecht S, Hecht R, Li YS, Lindberg RA, Chen JL, Jung DY, Zhang Z, Ko HJ, Kim JK, Veniant MM. Fibroblast growth factor 21 reverses hepatic steatosis, increases energy expenditure, and improves insulin sensitivity in diet-induced obese mice. Diabetes. 2009; 58:250–259.
64. Holland WL, Adams AC, Brozinick JT, Bui HH, Miyauchi Y, Kusminski CM, Bauer SM, Wade M, Singhal E, Cheng CC, Volk K, Kuo MS, Gordillo R, Kharitonenkov A, Scherer PE. An FGF21-adiponectin-ceramide axis controls energy expenditure and insulin action in mice. Cell Metab. 2013; 17:790–797.
65. Pathak P, Chiang JYL. Sterol 12α-hydroxylase aggravates dyslipidemia by activating the ceramide/mTORC1/SREBP1C pathway via FGF21 and FGF15. Gene Expr. 2019; 03. 19. DOI: 10.3727/105221619X15529371970455. [Epub].
66. Li T, Chanda D, Zhang Y, Choi HS, Chiang JY. Glucose stimulates cholesterol 7alpha-hydroxylase gene transcription in human hepatocytes. J Lipid Res. 2010; 51:832–842.
67. Li T, Francl JM, Boehme S, Ochoa A, Zhang Y, Klaassen CD, Erickson SK, Chiang JY. Glucose and insulin induction of bile acid synthesis: mechanisms and implication in diabetes and obesity. J Biol Chem. 2012; 287:1861–1873.
68. Slatis K, Gafvels M, Kannisto K, Ovchinnikova O, Paulsson-Berne G, Parini P, Jiang ZY, Eggertsen G. Abolished synthesis of cholic acid reduces atherosclerotic development in apolipoprotein E knockout mice. J Lipid Res. 2010; 51:3289–3298.
69. Kaur A, Patankar JV, de Haan W, Ruddle P, Wijesekara N, Groen AK, Verchere CB, Singaraja RR, Hayden MR. Loss of Cyp8b1 improves glucose homeostasis by increasing GLP-1. Diabetes. 2015; 64:1168–1179.
70. Bertaggia E, Jensen KK, Castro-Perez J, Xu Y, Di Paolo G, Chan RB, Wang L, Haeusler RA. Cyp8b1 ablation prevents Western diet-induced weight gain and hepatic steatosis because of impaired fat absorption. Am J Physiol Endocrinol Metab. 2017; 313:E121–E133.
71. Sayin SI, Wahlstrom A, Felin J, Jantti S, Marschall HU, Bamberg K, Angelin B, Hyotylainen T, Oresic M, Backhed F. Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist. Cell Metab. 2013; 17:225–235.
72. Wahlstrom A, Sayin SI, Marschall HU, Backhed F. Intestinal Crosstalk between bile acids and microbiota and its impact on host metabolism. Cell Metab. 2016; 24:41–50.
73. Tripathi A, Debelius J, Brenner DA, Karin M, Loomba R, Schnabl B, Knight R. The gut-liver axis and the intersection with the microbiome. Nat Rev Gastroenterol Hepatol. 2018; 15:397–411.
74. Ikegami T, Honda A. Reciprocal interactions between bile acids and gut microbiota in human liver diseases. Hepatol Res. 2018; 48:15–27.
75. Patterson E, Ryan PM, Cryan JF, Dinan TG, Ross RP, Fitzgerald GF, Stanton C. Gut microbiota, obesity and diabetes. Postgrad Med J. 2016; 92:286–300.
76. Gao Z, Yin J, Zhang J, Ward RE, Martin RJ, Lefevre M, Cefalu WT, Ye J. Butyrate improves insulin sensitivity and increases energy expenditure in mice. Diabetes. 2009; 58:1509–1517.
77. Qin J, Li Y, Cai Z, Li S, Zhu J, Zhang F, Liang S, Zhang W, Guan Y, Shen D, Peng Y, Zhang D, Jie Z, Wu W, Qin Y, Xue W, Li J, Han L, Lu D, Wu P, Dai Y, Sun X, Li Z, Tang A, Zhong S, Li X, Chen W, Xu R, Wang M, Feng Q, Gong M, Yu J, Zhang Y, Zhang M, Hansen T, Sanchez G, Raes J, Falony G, Okuda S, Almeida M, LeChatelier E, Renault P, Pons N, Batto JM, Zhang Z, Chen H, Yang R, Zheng W, Li S, Yang H, Wang J, Ehrlich SD, Nielsen R, Pedersen O, Kristiansen K, Wang J. A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature. 2012; 490:55–60.
78. David LA, Maurice CF, Carmody RN, Gootenberg DB, Button JE, Wolfe BE, Ling AV, Devlin AS, Varma Y, Fischbach MA, Biddinger SB, Dutton RJ, Turnbaugh PJ. Diet rapidly and reproducibly alters the human gut microbiome. Nature. 2014; 505:559–563.
79. Devkota S, Wang Y, Musch MW, Leone V, Fehlner-Peach H, Nadimpalli A, Antonopoulos DA, Jabri B, Chang EB. Dietary-fat-induced taurocholic acid promotes pathobiont expansion and colitis in Il10-/- mice. Nature. 2012; 487:104–108.
80. Patankar JV, Wong CK, Morampudi V, Gibson WT, Vallance B, Ioannou GN, Hayden MR. Genetic ablation of Cyp8b1 preserves host metabolic function by repressing steatohepatitis and altering gut microbiota composition. Am J Physiol Endocrinol Metab. 2018; 314:E418–E432.
81. Chevre R, Trigueros-Motos L, Castano D, Chua T, Corliano M, Patankar JV, Sng L, Sim L, Juin TL, Carissimo G, Ng LFP, Yi CNJ, Eliathamby CC, Groen AK, Hayden MR, Singaraja RR. Therapeutic modulation of the bile acid pool by Cyp8b1 knockdown protects against nonalcoholic fatty liver disease in mice. FASEB J. 2018; 32:3792–3802.
82. Gonzalez FJ, Jiang C, Patterson AD. An intestinal microbiota-farnesoid X receptor axis modulates metabolic disease. Gastroenterology. 2016; 151:845–859.
83. Jiang C, Xie C, Li F, Zhang L, Nichols RG, Krausz KW, Cai J, Qi Y, Fang ZZ, Takahashi S, Tanaka N, Desai D, Amin SG, Albert I, Patterson AD, Gonzalez FJ. Intestinal farnesoid X receptor signaling promotes nonalcoholic fatty liver disease. J Clin Invest. 2015; 125:386–402.
84. Jiang C, Xie C, Lv Y, Li J, Krausz KW, Shi J, Brocker CN, Desai D, Amin SG, Bisson WH, Liu Y, Gavrilova O, Patterson AD, Gonzalez FJ. Intestine-selective farnesoid X receptor inhibition improves obesity-related metabolic dysfunction. Nat Commun. 2015; 6:10166.
85. Xie C, Jiang C, Shi J, Gao X, Sun D, Sun L, Wang T, Takahashi S, Anitha M, Krausz KW, Patterson AD, Gonzalez FJ. An intestinal farnesoid X receptor-ceramide signaling axis modulates hepatic gluconeogenesis in mice. Diabetes. 2017; 66:613–626.
86. Parseus A, Sommer N, Sommer F, Caesar R, Molinaro A, Stahlman M, Greiner TU, Perkins R, Backhed F. Microbiota-induced obesity requires farnesoid X receptor. Gut. 2017; 66:429–437.
87. Sun L, Xie C, Wang G, Wu Y, Wu Q, Wang X, Liu J, Deng Y, Xia J, Chen B, Zhang S, Yun C, Lian G, Zhang X, Zhang H, Bisson WH, Shi J, Gao X, Ge P, Liu C, Krausz KW, Nichols RG, Cai J, Rimal B, Patterson AD, Wang X, Gonzalez FJ, Jiang C. Gut microbiota and intestinal FXR mediate the clinical benefits of metformin. Nat Med. 2018; 24:1919–1929.
88. Fang S, Suh JM, Reilly SM, Yu E, Osborn O, Lackey D, Yoshihara E, Perino A, Jacinto S, Lukasheva Y, Atkins AR, Khvat A, Schnabl B, Yu RT, Brenner DA, Coulter S, Liddle C, Schoonjans K, Olefsky JM, Saltiel AR, Downes M, Evans RM. Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance. Nat Med. 2015; 21:159–165.
89. Pathak P, Xie C, Nichols RG, Ferrell JM, Boehme S, Krausz KW, Patterson AD, Gonzalez FJ, Chiang JYL. Intestine farnesoid X receptor agonist and the gut microbiota activate G-protein bile acid receptor-1 signaling to improve metabolism. Hepatology. 2018; 68:1574–1588.
90. Yang JY, Lee YS, Kim Y, Lee SH, Ryu S, Fukuda S, Hase K, Yang CS, Lim HS, Kim MS, Kim HM, Ahn SH, Kwon BE, Ko HJ, Kweon MN. Gut commensal Bacteroides acidifaciens prevents obesity and improves insulin sensitivity in mice. Mucosal Immunol. 2017; 10:104–116.
91. Nauck MA. Incretin-based therapies for type 2 diabetes mellitus: properties, functions, and clinical implications. Am J Med. 2011; 124:1 Suppl. S3–S18.
92. Ahren B, Landin-Olsson M, Jansson PA, Svensson M, Holmes D, Schweizer A. Inhibition of dipeptidyl peptidase-4 reduces glycemia, sustains insulin levels, and reduces glucagon levels in type 2 diabetes. J Clin Endocrinol Metab. 2004; 89:2078–2084.
93. Trabelsi MS, Daoudi M, Prawitt J, Ducastel S, Touche V, Sayin SI, Perino A, Brighton CA, Sebti Y, Kluza J, Briand O, Dehondt H, Vallez E, Dorchies E, Baud G, Spinelli V, Hennuyer N, Caron S, Bantubungi K, Caiazzo R, Reimann F, Marchetti P, Lefebvre P, Backhed F, Gribble FM, Schoonjans K, Pattou F, Tailleux A, Staels B, Lestavel S. Farnesoid X receptor inhibits glucagon-like peptide-1 production by enteroendocrine L cells. Nat Commun. 2015; 6:7629.
94. Schauer PR, Bhatt DL, Kirwan JP, Wolski K, Aminian A, Brethauer SA, Navaneethan SD, Singh RP, Pothier CE, Nissen SE, Kashyap SR. STAMPEDE Investigators. Bariatric surgery versus intensive medical therapy for diabetes: 5-year outcomes. N Engl J Med. 2017; 376:641–651.
95. Patti ME, Houten SM, Bianco AC, Bernier R, Larsen PR, Holst JJ, Badman MK, Maratos-Flier E, Mun EC, Pihlajamaki J, Auwerx J, Goldfine AB. Serum bile acids are higher in humans with prior gastric bypass: potential contribution to improved glucose and lipid metabolism. Obesity (Silver Spring). 2009; 17:1671–1677.
96. Pournaras DJ, Glicksman C, Vincent RP, Kuganolipava S, Alaghband-Zadeh J, Mahon D, Bekker JH, Ghatei MA, Bloom SR, Walters JR, Welbourn R, le Roux CW. The role of bile after Roux-en-Y gastric bypass in promoting weight loss and improving glycaemic control. Endocrinology. 2012; 153:3613–3619.
97. Risstad H, Kristinsson JA, Fagerland MW, le Roux CW, Birkeland KI, Gulseth HL, Thorsby PM, Vincent RP, Engstrom M, Olbers T, Mala T. Bile acid profiles over 5 years after gastric bypass and duodenal switch: results from a randomized clinical trial. Surg Obes Relat Dis. 2017; 13:1544–1553.
98. Simonen M, Dali-Youcef N, Kaminska D, Venesmaa S, Kakela P, Paakkonen M, Hallikainen M, Kolehmainen M, Uusitupa M, Moilanen L, Laakso M, Gylling H, Patti ME, Auwerx J, Pihlajamaki J. Conjugated bile acids associate with altered rates of glucose and lipid oxidation after Roux-en-Y gastric bypass. Obes Surg. 2012; 22:1473–1480.
99. Nemati R, Lu J, Dokpuang D, Booth M, Plank LD, Murphy R. Increased bile acids and FGF19 after sleeve gastrectomy and Roux-en-Y gastric bypass correlate with improvement in type 2 diabetes in a randomized trial. Obes Surg. 2018; 28:2672–2686.
100. Bozadjieva N, Heppner KM, Seeley RJ. Targeting FXR and FGF19 to treat metabolic diseases-lessons learned from bariatric surgery. Diabetes. 2018; 67:1720–1728.
101. Gerhard GS, Styer AM, Wood GC, Roesch SL, Petrick AT, Gabrielsen J, Strodel WE, Still CD, Argyropoulos G. A role for fibroblast growth factor 19 and bile acids in diabetes remission after Roux-en-Y gastric bypass. Diabetes Care. 2013; 36:1859–1864.
102. Gomez-Ambrosi J, Gallego-Escuredo JM, Catalan V, Rodriguez A, Domingo P, Moncada R, Valenti V, Salvador J, Giralt M, Villarroya F, Fruhbeck G. FGF19 and FGF21 serum concentrations in human obesity and type 2 diabetes behave differently after diet- or surgically-induced weight loss. Clin Nutr. 2017; 36:861–868.
103. Ryan KK, Tremaroli V, Clemmensen C, Kovatcheva-Datchary P, Myronovych A, Karns R, Wilson-Perez HE, Sandoval DA, Kohli R, Backhed F, Seeley RJ. FXR is a molecular target for the effects of vertical sleeve gastrectomy. Nature. 2014; 509:183–188.
104. McGavigan AK, Garibay D, Henseler ZM, Chen J, Bettaieb A, Haj FG, Ley RE, Chouinard ML, Cummings BP. TGR5 contributes to glucoregulatory improvements after vertical sleeve gastrectomy in mice. Gut. 2017; 66:226–234.
105. Albaugh VL, Banan B, Antoun J, Xiong Y, Guo Y, Ping J, Alikhan M, Clements BA, Abumrad NN, Flynn CR. Role of bile acids and GLP-1 in mediating the metabolic improvements of bariatric surgery. Gastroenterology. 2019; 156:1041–1051.
106. Dao MC, Everard A, Aron-Wisnewsky J, Sokolovska N, Prifti E, Verger EO, Kayser BD, Levenez F, Chilloux J, Hoyles L. MICRO-Obes Consortium. Dumas ME, Rizkalla SW, Dore J, Cani PD, Clement K. Akkermansia muciniphila and improved metabolic health during a dietary intervention in obesity: relationship with gut microbiome richness and ecology. Gut. 2016; 65:426–436.
107. Schneeberger M, Everard A, Gomez-Valades AG, Matamoros S, Ramirez S, Delzenne NM, Gomis R, Claret M, Cani PD. Akkermansia muciniphila inversely correlates with the onset of inflammation, altered adipose tissue metabolism and metabolic disorders during obesity in mice. Sci Rep. 2015; 5:16643.
108. Adrian TE, Gariballa S, Parekh KA, Thomas SA, Saadi H, Al Kaabi J, Nagelkerke N, Gedulin B, Young AA. Rectal taurocholate increases L cell and insulin secretion, and decreases blood glucose and food intake in obese type 2 diabetic volunteers. Diabetologia. 2012; 55:2343–2347.
109. Mueller M, Thorell A, Claudel T, Jha P, Koefeler H, Lackner C, Hoesel B, Fauler G, Stojakovic T, Einarsson C, Marschall HU, Trauner M. Ursodeoxycholic acid exerts farnesoid X receptor-antagonistic effects on bile acid and lipid metabolism in morbid obesity. J Hepatol. 2015; 62:1398–1404.
110. Hirschfield GM, Mason A, Luketic V, Lindor K, Gordon SC, Mayo M, Kowdley KV, Vincent C, Bodhenheimer HC Jr, Pares A, Trauner M, Marschall HU, Adorini L, Sciacca C, Beecher-Jones T, Castelloe E, Bohm O, Shapiro D. Efficacy of obeticholic acid in patients with primary biliary cirrhosis and inadequate response to ursodeoxycholic acid. Gastroenterology. 2015; 148:751–761.
111. Neuschwander-Tetri BA, Loomba R, Sanyal AJ, Lavine JE, Van Natta ML, Abdelmalek MF, Chalasani N, Dasarathy S, Diehl AM, Hameed B, Kowdley KV, McCullough A, Terrault N, Clark JM, Tonascia J, Brunt EM, Kleiner DE, Doo E. NASH Clinical Research Network. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet. 2015; 385:956–965.
112. Friedman ES, Li Y, Shen TD, Jiang J, Chau L, Adorini L, Babakhani F, Edwards J, Shapiro D, Zhao C, Carr RM, Bittinger K, Li H, Wu GD. FXR-dependent modulation of the human small intestinal microbiome by the bile acid derivative obeticholic acid. Gastroenterology. 2018; 155:1741–1752.
113. Thomas C, Pellicciari R, Pruzanski M, Auwerx J, Schoonjans K. Targeting bile-acid signalling for metabolic diseases. Nat Rev Drug Discov. 2008; 7:678–693.
114. Pellicciari R, Gioiello A, Macchiarulo A, Thomas C, Rosatelli E, Natalini B, Sardella R, Pruzanski M, Roda A, Pastorini E, Schoonjans K, Auwerx J. Discovery of 6alpha-ethyl-23(S)-methylcholic acid (S-EMCA, INT-777) as a potent and selective agonist for the TGR5 receptor, a novel target for diabesity. J Med Chem. 2009; 52:7958–7961.
115. Pols TW, Nomura M, Harach T, Lo Sasso G, Oosterveer MH, Thomas C, Rizzo G, Gioiello A, Adorini L, Pellicciari R, Auwerx J, Schoonjans K. TGR5 activation inhibits atherosclerosis by reducing macrophage inflammation and lipid loading. Cell Metab. 2011; 14:747–757.
116. Cipriani S, Mencarelli A, Chini MG, Distrutti E, Renga B, Bifulco G, Baldelli F, Donini A, Fiorucci S. The bile acid receptor GPBAR-1 (TGR5) modulates integrity of intestinal barrier and immune response to experimental colitis. PLoS One. 2011; 6:e25637.
117. Carino A, Cipriani S, Marchiano S, Biagioli M, Santorelli C, Donini A, Zampella A, Monti MC, Fiorucci S. BAR502, a dual FXR and GPBAR1 agonist, promotes browning of white adipose tissue and reverses liver steatosis and fibrosis. Sci Rep. 2017; 7:42801.
118. Zambad SP, Tuli D, Mathur A, Ghalsasi SA, Chaudhary AR, Deshpande S, Gupta RC, Chauthaiwale V, Dutt C. TRC210258, a novel TGR5 agonist, reduces glycemic and dyslipidemic cardiovascular risk in animal models of diabesity. Diabetes Metab Syndr Obes. 2013; 7:1–14.
119. Miyazaki-Anzai S, Masuda M, Kohno S, Levi M, Shiozaki Y, Keenan AL, Miyazaki M. Simultaneous inhibition of FXR and TGR5 exacerbates atherosclerotic formation. J Lipid Res. 2018; 59:1709–1713.
120. Ferrell JM, Pathak P, Boehme S, Gilliland T, Chiang JYL. Deficiency of both farnesoid X receptor and takeda g protein-coupled receptor 5 exacerbated liver fibrosis in mice. Hepatology. 2019; 01. 21. DOI: 10.1002/hep.30513. [Epub].
121. Smushkin G, Sathananthan M, Piccinini F, Dalla Man C, Law JH, Cobelli C, Zinsmeister AR, Rizza RA, Vella A. The effect of a bile acid sequestrant on glucose metabolism in subjects with type 2 diabetes. Diabetes. 2013; 62:1094–1101.
122. Potthoff MJ, Potts A, He T, Duarte JA, Taussig R, Mangelsdorf DJ, Kliewer SA, Burgess SC. Colesevelam suppresses hepatic glycogenolysis by TGR5-mediated induction of GLP-1 action in DIO mice. Am J Physiol Gastrointest Liver Physiol. 2013; 304:G371–G380.
123. Herrema H, Meissner M, van Dijk TH, Brufau G, Boverhof R, Oosterveer MH, Reijngoud DJ, Muller M, Stellaard F, Groen AK, Kuipers F. Bile salt sequestration induces hepatic de novo lipogenesis through farnesoid X receptor- and liver X receptor alpha-controlled metabolic pathways in mice. Hepatology. 2010; 51:806–816.
124. Staels B, Kuipers F. Bile acid sequestrants and the treatment of type 2 diabetes mellitus. Drugs. 2007; 67:1383–1392.
125. Hansen M, Sonne DP, Mikkelsen KH, Gluud LL, Vilsboll T, Knop FK. Bile acid sequestrants for glycemic control in patients with type 2 diabetes: a systematic review with meta-analysis of randomized controlled trials. J Diabetes Complications. 2017; 31:918–927.
126. Fu L, John LM, Adams SH, Yu XX, Tomlinson E, Renz M, Williams PM, Soriano R, Corpuz R, Moffat B, Vandlen R, Simmons L, Foster J, Stephan JP, Tsai SP, Stewart TA. Fibroblast growth factor 19 increases metabolic rate and reverses dietary and leptin-deficient diabetes. Endocrinology. 2004; 145:2594–2603.
127. Perry RJ, Lee S, Ma L, Zhang D, Schlessinger J, Shulman GI. FGF1 and FGF19 reverse diabetes by suppression of the hypothalamic-pituitary-adrenal axis. Nat Commun. 2015; 6:6980.
128. Degirolamo C, Sabba C, Moschetta A. Therapeutic potential of the endocrine fibroblast growth factors FGF19, FGF21 and FGF23. Nat Rev Drug Discov. 2016; 15:51–69.
129. Zhou M, Learned RM, Rossi SJ, DePaoli AM, Tian H, Ling L. Engineered FGF19 eliminates bile acid toxicity and lipotoxicity leading to resolution of steatohepatitis and fibrosis in mice. Hepatol Commun. 2017; 1:1024–1042.
130. Zhang X, Yeung DC, Karpisek M, Stejskal D, Zhou ZG, Liu F, Wong RL, Chow WS, Tso AW, Lam KS, Xu A. Serum FGF21 levels are increased in obesity and are independently associated with the metabolic syndrome in humans. Diabetes. 2008; 57:1246–1253.
131. Yilmaz Y, Eren F, Yonal O, Kurt R, Aktas B, Celikel CA, Ozdogan O, Imeryuz N, Kalayci C, Avsar E. Increased serum FGF21 levels in patients with nonalcoholic fatty liver disease. Eur J Clin Invest. 2010; 40:887–892.
132. Kharitonenkov A, Shanafelt AB. FGF21: a novel prospect for the treatment of metabolic diseases. Curr Opin Investig Drugs. 2009; 10:359–364.
133. Talukdar S, Zhou Y, Li D, Rossulek M, Dong J, Somayaji V, Weng Y, Clark R, Lanba A, Owen BM, Brenner MB, Trimmer JK, Gropp KE, Chabot JR, Erion DM, Rolph TP, Goodwin B, Calle RA. A long-acting FGF21 molecule, PF-05231023, decreases body weight and improves lipid profile in non-human primates and type 2 diabetic subjects. Cell Metab. 2016; 23:427–440.
134. Talukdar S, Owen BM, Song P, Hernandez G, Zhang Y, Zhou Y, Scott WT, Paratala B, Turner T, Smith A, Bernardo B, Muller CP, Tang H, Mangelsdorf DJ, Goodwin B, Kliewer SA. FGF21 regulates sweet and alcohol preference. Cell Metab. 2016; 23:344–349.
135. Widlansky ME, Puppala VK, Suboc TM, Malik M, Branum A, Signorelli K, Wang J, Ying R, Tanner MJ, Tyagi S. Impact of DPP-4 inhibition on acute and chronic endothelial function in humans with type 2 diabetes on background metformin therapy. Vasc Med. 2017; 22:189–196.
136. Smits MM, van Raalte DH, Tonneijck L, Muskiet MH, Kramer MH, Cahen DL. GLP-1 based therapies: clinical implications for gastroenterologists. Gut. 2016; 65:702–711.
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