Lab Anim Res.  2018 Dec;34(4):140-146. 10.5625/lar.2018.34.4.140.

Crosstalk between FXR and TGR5 controls glucagon-like peptide 1 secretion to maintain glycemic homeostasis

• Kim H
• Fang S

• KMID: 2459289
• DOI: http://doi.org/10.5625/lar.2018.34.4.140

Abstract

Though bile acids have been well known as digestive juice, recent studies have demonstrated that bile acids bind to their endogenous receptors, including Farnesoid X receptor (FXR) and G protein-coupled bile acid receptor 1 (GPBAR1; TGR5) and serve as hormone to control various biological processes, including cholesterol/bile acid metabolism, glucose/lipid metabolism, immune responses, and energy metabolism. Deficiency of those bile acid receptors has been reported to induce diverse metabolic syndromes such as obesity, hyperlipidemia, hyperglycemia, and insulin resistance. As consistent, numerous studies have reported alteration of bile acid signaling pathways in type II diabetes patients. Interestingly, bile acids have shown to activate TGR5 in intestinal L cells and enhance secretion of glucagon-like peptide 1 (GLP-1) to potentiate insulin secretion in response to glucose. Moreover, FXR has been shown to crosstalk with TGR5 to control GLP-1 secretion. Altogether, bile acid receptors, FXR and TGR5 are potent therapeutic targets for the treatment of metabolic diseases, including type II diabetes.

Keyword

Bile acids; Farnesoid X receptor; G protein-coupled bile acid receptor; Glucagon-like peptide 1; obesity; diabetes

MeSH Terms

Bile
Bile Acids and Salts
Biological Processes
Energy Metabolism
Enteroendocrine Cells
Glucagon-Like Peptide 1*
Glucose
Homeostasis*
Humans
Hyperglycemia
Hyperlipidemias
Insulin
Insulin Resistance
Metabolic Diseases
Metabolism
Obesity
Bile Acids and Salts
Glucagon-Like Peptide 1
Glucose
Insulin

Figure

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  Figure 1 Structure of Nuclear receptor superfamily.

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  Figure 2 Transcriptional regulation by FXR in response to bile acids.

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  Figure 3 Bile acids activate TGR5 to control thermogenesis and energy expenditure in brown adipose tissue.

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  Figure 4 Bile acids activate TGR5 to enhance GLP-1 secretion in entoroendocrinal L cells.

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  Figure 5 Crosstalk between FXR and TGR5 to potentiate GLP-1 secretion for the maintenance of glycemic homeostasis.

Reference

1. Chiang JY. Bile acid regulation of gene expression: roles of nuclear hormone receptors. Endocr Rev. 2002; 23(4):443–463.

2. Li T, Chiang JY. Nuclear receptors in bile acid metabolism. Drug Metab Rev. 2013; 45(1):145–155.

3. Russell DW. The enzymes, regulation, and genetics of bile acid synthesis. Annu Rev Biochem. 2003; 72:137–174.

4. Lu TT, Makishima M, Repa JJ, Schoonjans K, Kerr TA, Auwerx J, Mangelsdorf DJ. Molecular basis for feedback regulation of bile acid synthesis by nuclear receptors. Mol Cell. 2000; 6(3):507–515.

5. 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(5418):1362–1365.

6. Watanabe M, Houten SM, Mataki C, Christoffolete MA, Kim BW, Sato H, Messaddeq N, Harney JW, Ezaki O, Kodama T, Schoonjans K, Bianco AC, Auwerx J. Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature. 2006; 439(7075):484–489.

7. 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(3):167–177.

8. Katsuma S, Hirasawa A, Tsujimoto G. Bile acids promote glucagon-like peptide-1 secretion through TGR5 in a murine enteroendocrine cell line STC-1. Biochem Biophys Res Commun. 2005; 329(1):386–390.

9. 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(26):11055–11069.

10. 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(4):1574–1588.

11. Hong SH, Ahmadian M, Yu RT, Atkins AR, Downes M, Evans RM. Nuclear receptors and metabolism: from feast to famine. Diabetologia. 2014; 57(5):860–867.

12. Yang X, Lamia KA, Evans RM. Nuclear receptors, metabolism, and the circadian clock. Cold Spring Harb Symp Quant Biol. 2007; 72:387–394.

13. Ordentlich P, Downes M, Evans RM. Corepressors and nuclear hormone receptor function. Curr Top Microbiol Immunol. 2001; 254:101–116.

14. McKenna NJ, Evans RM, O'Malley BW. Nuclear Receptor Signaling: a home for nuclear receptor and coregulator signaling research. Nucl Recept Signal. 2014; 12:e006.

15. Forman BM, Goode E, Chen J, Oro AE, Bradley DJ, Perlmann T, Noonan DJ, Burka LT, McMorris T, Lamph WW, Evans RM, Weinberger C. Identification of a nuclear receptor that is activated by farnesol metabolites. Cell. 1995; 81(5):687–693.

16. Edwards PA, Kast HR, Anisfeld AM. BAREing it all: the adoption of LXR and FXR and their roles in lipid homeostasis. J Lipid Res. 2002; 43(1):2–12.

17. Lee FY, Lee H, Hubbert ML, Edwards PA, Zhang Y. FXR, a multipurpose nuclear receptor. Trends Biochem Sci. 2006; 31(10):572–580.

18. Fang S, Tsang S, Jones R, Ponugoti B, Yoon H, Wu SY, Chiang CM, Willson TM, Kemper JK. The p300 acetylase is critical for ligand-activated farnesoid X receptor (FXR) induction of SHP. J Biol Chem. 2008; 283(50):35086–35095.

19. 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(4):1006–1011.

20. Renga B, Mencarelli A, Vavassori P, Brancaleone V, Fiorucci S. The bile acid sensor FXR regulates insulin transcription and secretion. Biochim Biophys Acta. 2010; 1802(3):363–372.

21. Ma K, Saha PK, Chan L, Moore DD. Farnesoid X receptor is essential for normal glucose homeostasis. J Clin Invest. 2006; 116(4):1102–1109.

22. Duran-Sandoval D, Cariou B, Percevault F, Hennuyer N, Grefhorst A, van Dijk TH, Gonzalez FJ, Fruchart JC, Kuipers F, Staels B. The farnesoid X receptor modulates hepatic carbohydrate metabolism during the fasting-refeeding transition. J Biol Chem. 2005; 280(33):29971–29979.

23. Jiang T, Wang XX, Scherzer P, Wilson P, Tallman J, Takahashi H, Li J, Iwahashi M, Sutherland E, Arend L, Levi M. Farnesoid X receptor modulates renal lipid metabolism, fibrosis, and diabetic nephropathy. Diabetes. 2007; 56(10):2485–2493.

24. Lambert G, Amar MJ, Guo G, Brewer HB Jr, Gonzalez FJ, Sinal CJ. The farnesoid X-receptor is an essential regulator of cholesterol homeostasis. J Biol Chem. 2003; 278(4):2563–2570.

25. Claudel T, Staels B, Kuipers F. The Farnesoid X receptor: a molecular link between bile acid and lipid and glucose metabolism. Arterioscler Thromb Vasc Biol. 2005; 25(10):2020–2030.

26. 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(10):e25637.

27. Keitel V, Donner M, Winandy S, Kubitz R, Häussinger D. Expression and function of the bile acid receptor TGR5 in Kupffer cells. Biochem Biophys Res Commun. 2008; 372(1):78–84.

28. Lou G, Ma X, Fu X, Meng Z, Zhang W, Wang YD, Van Ness C, Yu D, Xu R, Huang W. GPBAR1/TGR5 mediates bile acid-induced cytokine expression in murine Kupffer cells. PLoS One. 2014; 9(4):e93567.

29. Keitel V, Reinehr R, Gatsios P, Rupprecht C, Görg B, Selbach O, Häussinger D, Kubitz R. The G-protein coupled bile salt receptor TGR5 is expressed in liver sinusoidal endothelial cells. Hepatology. 2007; 45(3):695–704.

30. Duboc H, Taché Y, Hofmann AF. The bile acid TGR5 membrane receptor: from basic research to clinical application. Dig Liver Dis. 2014; 46(4):302–312.

31. Li P, Zhu L, Yang X, Li W, Sun X, Yi B, Zhu S. Farnesoid X Receptor (FXR) Interacts with Camp Response Element Binding Protein (CREB) to Modulate Glucagon-Like Peptide-1 (7-36) Amide (GLP-1) Secretion by Intestinal L Cell. Cell Physiol Biochem. 2018; 47(4):1442–1452.

32. Velazquez-Villegas LA, Perino A, Lemos V, Zietak M, Nomura M, Pols TWH, Schoonjans K. TGR5 signalling promotes mitochondrial fission and beige remodelling of white adipose tissue. Nat Commun. 2018; 9(1):245.

33. Trabelsi MS, Daoudi M, Prawitt J, Ducastel S, Touche V, Sayin SI, Perino A, Brighton CA4, 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, Bäckhed 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.

34. 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(2):159–165.

35. Ryan KK, Tremaroli V, Clemmensen C, Kovatcheva-Datchary P, Myronovych A, Karns R, Wilson-Pérez HE, Sandoval DA, Kohli R, Bäckhed F, Seeley RJ. FXR is a molecular target for the effects of vertical sleeve gastrectomy. Nature. 2014; 509(7499):183–188.

36. 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(7):1859–1864.

37. Kohli R, Bradley D, Setchell KD, Eagon JC, Abumrad N, Klein S. Weight loss induced by Roux-en-Y gastric bypass but not laparoscopic adjustable gastric banding increases circulating bile acids. J Clin Endocrinol Metab. 2013; 98(4):E708–E712.

38. Rabiee A, Magruder JT, Salas-Carrillo R, Carlson O, Egan JM, Askin FB, Elahi D, Andersen DK. Hyperinsulinemic hypoglycemia after Roux-en-Y gastric bypass: unraveling the role of gut hormonal and pancreatic endocrine dysfunction. J Surg Res. 2011; 167(2):199–205.