Abstract
Background: Diabetes, with an increased prevalence and various progressive complications, has become a significant global health challenge. The concrete mechanisms responsible for the development of diabetes still remain incompletely unknown, although substantial researches have been conducted to search for the effective therapeutic targets. This review aims to reveal the novel roles of Xenobiotic Nuclear Receptors (XNRs), including the Peroxisome Proliferator-Activated Receptor (PPAR), the Farnesoid X Receptor (FXR), the Liver X Receptor (LXR), the Pregnane X Receptor (PXR) and the Constitutive Androstane Receptor (CAR), in the development of diabetes and provide potential strategies for research and treatment of metabolic diseases.
Methods: We retrieved a large number of original data about these five XNRs and organized to focus on their recently discovered functions in diabetes and its complications.
Results: Increasing evidences have suggested that PPAR, FXR, LXR ,PXR and CAR are involved in the development of diabetes and its complications through different mechanisms, including the regulation of glucose and lipid metabolism, insulin and inflammation response and related others.
Conclusion: PPAR, FXR, LXR, PXR, and CAR, as the receptors for numerous natural or synthetic compounds, may be the most effective therapeutic targets in the treatment of metabolic diseases.
Keywords: Xenobiotic Nuclear Receptors (XNRs), Peroxisome Proliferator-Activated Receptor (PPAR), Farnesoid X Receptor (FXR), Liver X Receptor (LXR), Pregnane X Receptor (PXR), Constitutive Androstane Receptor (CAR), diabetes.
Graphical Abstract
[1]
Cho, N.H.; Shaw, J.E.; Karuranga, S.; Huang, Y.; da Rocha Fernandes, J.D.; Ohlrogge, A.W.; Malanda, B. IDF Diabetes Atlas: Global estimates of diabetes prevalence for 2017 and projections for 2045. Diabetes Res. Clin. Pract., 2018, 138, 271-281.
[3]
Odegaard, J.I.; Chawla, A. Pleiotropic actions of insulin resistance and inflammation in metabolic homeostasis. Science, 2013, 339(6116), 172-177.
[4]
Schmidt, A.; Endo, N.; Rutledge, S.J.; Vogel, R.; Shinar, D.; Rodan, G.A. Identification of a new member of the steroid hormone receptor superfamily that is activated by a peroxisome proliferator and fatty acids. Mol. Endocrinol., 1992, 6(10), 1634-1641.
[5]
Lehmann, J.M.; Kliewer, S.A.; Moore, L.B.; Smith-Oliver, T.A.; Oliver, B.B.; Su, J.L.; Sundseth, S.S.; Winegar, D.A.; Blanchard, D.E.; Spencer, T.A.; Willson, T.M. Activation of the nuclear receptor LXR by oxysterols defines a new hormone response pathway. J. Biol. Chem., 1997, 272(6), 3137-3140.
[6]
Parks, D.J.; Blanchard, S.G.; Bledsoe, R.K.; Chandra, G.; Consler, T.G.; Kliewer, S.A.; Stimmel, J.B.; Willson, T.M.; Zavacki, A.M.; Moore, D.D.; Lehmann, J.M. Bile acids: natural ligands for an orphan nuclear receptor. Science, 1999, 284(5418), 1365-1368.
[8]
Clinckemalie, L.; Vanderschueren, D.; Boonen, S.; Claessens, F. The hinge region in androgen receptor control. Mol. Cell. Endocrinol., 2012, 358(1), 1-8.
[9]
Gronemeyer, H.; Gustafsson, J.A.; Laudet, V. Principles for modulation of the nuclear receptor superfamily. Nat. Rev. Drug Discov., 2004, 3(11), 950-964.
[10]
Fujita, A.; Mitsuhashi, T. Differential regulation of ligand-dependent and ligand-independent functions of the mouse retinoid X receptor beta by alternative splicing. Biochem. Biophys. Res. Commun., 1999, 255(3), 625-630.
[11]
Wallace, B.D.; Betts, L.; Talmage, G.; Pollet, R.M.; Holman, N.S.; Redinbo, M.R. Structural and functional analysis of the human nuclear xenobiotic receptor PXR in complex with RXRα. J. Mol. Biol., 2013, 425(14), 2561-2577.
[12]
Heery, D.M.; Hoare, S.; Hussain, S.; Parker, M.G.; Sheppard, H. Core LXXLL motif sequences in CREB-binding protein, SRC1, and RIP140 define affinity and selectivity for steroid and retinoid receptors. J. Biol. Chem., 2001, 276(9), 6695-6702.
[13]
Hu, X.; Lazar, M.A. The CoRNR motif controls the recruitment of corepressors by nuclear hormone receptors. Nature, 1999, 402(6757), 93-96.
[14]
Dreyer, C.; Krey, G.; Keller, H.; Givel, F.; Helftenbein, G.; Wahli, W. Control of the peroxisomal beta-oxidation pathway by a novel family of nuclear hormone receptors. Cell, 1992, 68(5), 879-887.
[15]
Issemann, I.; Green, S. Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators. Nature, 1990, 347(6294), 645-650.
[16]
Mukherjee, R.; Jow, L.; Croston, G.E.; Paterniti, J.R. Jr Identification, characterization, and tissue distribution of human peroxisome Proliferator-Activated Receptor (PPAR) isoforms PPARgamma2 versus PPARgamma1 and activation with retinoid X receptor agonists and antagonists. J. Biol. Chem., 1997, 272(12), 8071-8076.
[17]
Fajas, L.; Fruchart, J.C.; Auwerx, J. PPARgamma3 mRNA: A distinct PPARgamma mRNA subtype transcribed from an independent promoter. FEBS Lett., 1998, 438(1-2), 55-60.
[18]
Sundvold, H.; Lien, S. Identification of a novel peroxisome Proliferator-Activated Receptor (PPAR) gamma promoter in man and transactivation by the nuclear receptor RORalpha1. Biochem. Biophys. Res. Commun., 2001, 287(2), 383-390.
[19]
Chen, Y.; Jimenez, A.R.; Medh, J.D. Identification and regulation of novel PPAR-gamma splice variants in human THP-1 macrophages. Biochim. Biophys. Acta, 2006, 1759(1-2), 32-43.
[20]
DeFronzo, R.A.; Tripathy, D.; Schwenke, D.C.; Banerji, M.; Bray, G.A.; Buchanan, T.A.; Clement, S.C.; Henry, R.R.; Hodis, H.N.; Kitabchi, A.E.; Mack, W.J.; Mudaliar, S.; Ratner, R.E.; Williams, K.; Stentz, F.B.; Musi, N.; Reaven, P.D. Pioglitazone for diabetes prevention in impaired glucose tolerance. N. Engl. J. Med., 2011, 364(12), 1104-1115.
[21]
Cusi, K.; Orsak, B.; Bril, F.; Lomonaco, R.; Hecht, J.; Ortiz-Lopez, C.; Tio, F.; Hardies, J.; Darland, C.; Musi, N.; Webb, A.; Portillo-Sanchez, P. Long-term pioglitazone treatment for patients with nonalcoholic steatohepatitis and prediabetes or type 2 diabetes mellitus: A randomized trial. Ann. Intern. Med., 2016, 165(5), 305-315.
[22]
Kramer, D.; Shapiro, R.; Adler, A.; Bush, E.; Rondinone, C.M. Insulin-sensitizing effect of rosiglitazone (BRL-49653) by regulation of glucose transporters in muscle and fat of Zucker rats. Metabolism, 2001, 50(11), 1294-1300.
[23]
Festuccia, W.T.; Blanchard, P.G.; Turcotte, V.; Laplante, M.; Sariahmetoglu, M.; Brindley, D.N.; Deshaies, Y. Depot-specific effects of the PPARgamma agonist rosiglitazone on adipose tissue glucose uptake and metabolism. J. Lipid Res., 2009, 50(6), 1185-1194.
[24]
Saitoh, Y.; Chun-ping, C.; Noma, K.; Ueno, H.; Mizuta, M.; Nakazato, M. Pioglitazone attenuates fatty acid-induced oxidative stress and apoptosis in pancreatic beta-cells. Diabetes Obes. Metab., 2008, 10(7), 564-573.
[25]
Patsouris, D.; Neels, J.G.; Fan, W.; Li, P.P.; Nguyen, M.T.; Olefsky, J.M. Glucocorticoids and thiazolidinediones interfere with adipocyte-mediated macrophage chemotaxis and recruitment. J. Biol. Chem., 2009, 284(45), 31223-31235.
[26]
Cipolletta, D.; Feuerer, M.; Li, A.; Kamei, N.; Lee, J.; Shoelson, S.E.; Benoist, C.; Mathis, D. PPAR-γ is a major driver of the accumulation and phenotype of adipose tissue Treg cells. Nature, 2012, 486(7404), 549-553.
[27]
Ryan, K.K.; Li, B.; Grayson, B.E.; Matter, E.K.; Woods, S.C.; Seeley, R.J. A role for central nervous system PPAR-γ in the regulation of energy balance. Nat. Med., 2011, 17(5), 623-626.
[28]
Beck, G.R., Jr; Khazai, N.B.; Bouloux, G.F.; Camalier, C.E.; Lin, Y.; Garneys, L.M.; Siqueira, J.; Peng, L.; Pasquel, F.; Umpierrez, D.; Smiley, D.; Umpierrez, G.E. The effects of thiazolidinediones on human bone marrow stromal cell differentiation in vitro and in thiazolidinedione-treated patients with type 2 diabetes. Transl. Res., 2013, 161(3), 145-155.
[29]
Nissen, S.E.; Wolski, K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N. Engl. J. Med., 2007, 356(24), 2457-2471.
[30]
Graham, D.J.; Ouellet-Hellstrom, R. MaCurdy, T.E.; Ali, F.; Sholley, C.; Worrall, C.; Kelman, J.A. Risk of acute myocardial infarction, stroke, heart failure, and death in elderly Medicare patients treated with rosiglitazone or pioglitazone. JAMA, 2010, 304(4), 411-418.
[31]
Lago, R.M.; Singh, P.P.; Nesto, R.W. Congestive heart failure and cardiovascular death in patients with prediabetes and type 2 diabetes given thiazolidinediones: a meta-analysis of randomised clinical trials. Lancet, 2007, 370(9593), 1129-1136.
[32]
Davis, T.M.; Yeap, B.B.; Davis, W.A.; Bruce, D.G. Lipid-lowering therapy and peripheral sensory neuropathy in type 2 diabetes: the Fremantle Diabetes Study. Diabetologia, 2008, 51(4), 562-566.
[33]
Keech, A.; Simes, R.J.; Barter, P.; Best, J.; Scott, R.; Taskinen, M.R.; Forder, P.; Pillai, A.; Davis, T.; Glasziou, P.; Drury, P.; Kesäniemi, Y.A.; Sullivan, D.; Hunt, D.; Colman, P.; d’Emden, M.; Whiting, M.; Ehnholm, C.; Laakso, M. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet, 2005, 366(9500), 1849-1861.
[34]
Hiukka, A.; Westerbacka, J.; Leinonen, E.S.; Watanabe, H.; Wiklund, O.; Hulten, L.M.; Salonen, J.T.; Tuomainen, T.P.; Yki-Järvinen, H.; Keech, A.C.; Taskinen, M.R. Long-term effects of fenofibrate on carotid intima-media thickness and augmentation index in subjects with type 2 diabetes mellitus. J. Am. Coll. Cardiol., 2008, 52(25), 2190-2197.
[35]
Brunmair, B.; Staniek, K.; Dörig, J.; Szöcs, Z.; Stadlbauer, K.; Marian, V.; Gras, F.; Anderwald, C.; Nohl, H.; Waldhäusl, W.; Fürnsinn, C. Activation of PPAR-delta in isolated rat skeletal muscle switches fuel preference from glucose to fatty acids. Diabetologia, 2006, 49(11), 2713-2722.
[36]
Risérus, U.; Sprecher, D.; Johnson, T.; Olson, E.; Hirschberg, S.; Liu, A.; Fang, Z.; Hegde, P.; Richards, D.; Sarov-Blat, L.; Strum, J.C.; Basu, S.; Cheeseman, J.; Fielding, B.A.; Humphreys, S.M.; Danoff, T.; Moore, N.R.; Murgatroyd, P.; O’Rahilly, S.; Sutton, P.; Willson, T.; Hassall, D.; Frayn, K.N.; Karpe, F. Activation of peroxisome proliferator-activated receptor (PPAR)delta promotes reversal of multiple metabolic abnormalities, reduces oxidative stress, and increases fatty acid oxidation in moderately obese men. Diabetes, 2008, 57(2), 332-339.
[37]
Mottillo, E.P.; Bloch, A.E.; Leff, T.; Granneman, J.G. Lipolytic products activate peroxisome proliferator-activated receptor (PPAR) α and δ in brown adipocytes to match fatty acid oxidation with supply. J. Biol. Chem., 2012, 287(30), 25038-25048.
[38]
Qin, X.; Xie, X.; Fan, Y.; Tian, J.; Guan, Y.; Wang, X.; Zhu, Y.; Wang, N. Peroxisome proliferator-activated receptor-delta induces insulin-induced gene-1 and suppresses hepatic lipogenesis in obese diabetic mice. Hepatology, 2008, 48(2), 432-441.
[39]
Choi, K.C.; Lee, S.Y.; Yoo, H.J.; Ryu, O.H.; Lee, K.W.; Kim, S.M.; Baik, S.H.; Choi, K.M. Effect of PPAR-delta agonist on the expression of visfatin, adiponectin, and resistin in rat adipose tissue and 3T3-L1 adipocytes. Biochem. Biophys. Res. Commun., 2007, 357(1), 62-67.
[40]
Salvadó, L.; Barroso, E.; Gómez-Foix, A.M.; Palomer, X.; Michalik, L.; Wahli, W.; Vázquez-Carrera, M. PPARβ/δ prevents endoplasmic reticulum stress-associated inflammation and insulin resistance in skeletal muscle cells through an AMPK-dependent mechanism. Diabetologia, 2014, 57(10), 2126-2135.
[41]
Zhang, J.; Liu, X.; Xie, X.B.; Cheng, X.C.; Wang, R.L. Multitargeted bioactive ligands for PPARs discovered in the last decade. Chem. Biol. Drug Des., 2016, 88(5), 635-663.
[42]
Willy, P.J.; Umesono, K.; Ong, E.S.; Evans, R.M.; Heyman, R.A.; Mangelsdorf, D.J. LXR, a nuclear receptor that defines a distinct retinoid response pathway. Genes Dev., 1995, 9(9), 1033-1045.
[43]
Apfel, R.; Benbrook, D.; Lernhardt, E.; Ortiz, M.A.; Salbert, G.; Pfahl, M. A novel orphan receptor specific for a subset of thyroid hormone-responsive elements and its interaction with the retinoid/thyroid hormone receptor subfamily. Mol. Cell. Biol., 1994, 14(10), 7025-7035.
[44]
Lu, T.T.; Repa, J.J.; Mangelsdorf, D.J. Orphan nuclear receptors as eLiXiRs and FiXeRs of sterol metabolism. J. Biol. Chem., 2001, 276(41), 37735-37738.
[45]
Peet, D.J.; Turley, S.D.; Ma, W.; Janowski, B.A.; Lobaccaro, J.M.; Hammer, R.E.; Mangelsdorf, D.J. Cholesterol and bile acid metabolism are impaired in mice lacking the nuclear oxysterol receptor LXR alpha. Cell, 1998, 93(5), 693-704.
[46]
Cao, G.; Liang, Y.; Broderick, C.L.; Oldham, B.A.; Beyer, T.P.; Schmidt, R.J.; Zhang, Y.; Stayrook, K.R.; Suen, C.; Otto, K.A.; Miller, A.R.; Dai, J.; Foxworthy, P.; Gao, H.; Ryan, T.P.; Jiang, X.C.; Burris, T.P.; Eacho, P.I.; Etgen, G.J. Antidiabetic action of a liver x receptor agonist mediated by inhibition of hepatic gluconeogenesis. J. Biol. Chem., 2003, 278(2), 1131-1136.
[47]
Liu, Y.; Yan, C.; Wang, Y.; Nakagawa, Y.; Nerio, N.; Anghel, A.; Lutfy, K.; Friedman, T.C. Liver X receptor agonist T0901317 inhibition of glucocorticoid receptor expression in hepatocytes may contribute to the amelioration of diabetic syndrome in db/db mice. Endocrinology, 2006, 147(11), 5061-5068.
[48]
Dong, Y.; Gao, G.; Fan, H.; Li, S.; Li, X.; Liu, W. Activation of the Liver X Receptor by Agonist TO901317 Improves Hepatic Insulin Resistance via Suppressing Reactive Oxygen Species and JNK Pathway. PLoS One, 2015, 10(4), e0124778.
[49]
Gao, M.; Zhang, C.; Ma, Y.; Liu, D. Cold Exposure Improves the Anti-diabetic Effect of T0901317 in Streptozotocin-Induced Diabetic Mice. AAPS J., 2015, 17(3), 700-710.
[50]
Laffitte, B.A.; Chao, L.C.; Li, J.; Walczak, R.; Hummasti, S.; Joseph, S.B.; Castrillo, A.; Wilpitz, D.C.; Mangelsdorf, D.J.; Collins, J.L.; Saez, E.; Tontonoz, P. Activation of liver X receptor improves glucose tolerance through coordinate regulation of glucose metabolism in liver and adipose tissue. Proc. Natl. Acad. Sci. USA, 2003, 100(9), 5419-5424.
[51]
Weems, J.C.; Griesel, B.A.; Olson, A.L. Class II histone deacetylases downregulate GLUT4 transcription in response to increased cAMP signaling in cultured adipocytes and fasting mice. Diabetes, 2012, 61(6), 1404-1414.
[52]
Baranowski, M.; Zabielski, P.; Błachnio-Zabielska, A.U.; Harasim, E.; Chabowski, A.; Górski, J. Insulin-sensitizing effect of LXR agonist T0901317 in high-fat fed rats is associated with restored muscle GLUT4 expression and insulin-stimulated AS160 phosphorylation. Cell. Physiol. Biochem., 2014, 33(4), 1047-1057.
[53]
Pettersson, A.M.; Stenson, B.M.; Lorente-Cebrián, S.; Andersson, D.P.; Mejhert, N.; Krätzel, J.; Aström, G.; Dahlman, I.; Chibalin, A.V.; Arner, P.; Laurencikiene, J. LXR is a negative regulator of glucose uptake in human adipocytes. Diabetologia, 2013, 56(9), 2044-2054.
[54]
Bełtowski, J.; Liver, X. Receptors (LXR) as therapeutic targets in dyslipidemia. Cardiovasc. Ther., 2008, 26(4), 297-316.
[55]
Athithan, V.; Srikumar, K. 28-Homocastasterone down regulates blood glucose, cholesterol, triglycerides, SREBP1c and activates LxR expression in normal & diabetic male rat. Chem. Biol. Interact., 2017, 277, 8-20.
[56]
Briand, O.; Touche, V.; Colin, S.; Brufau, G.; Davalos, A.; Schonewille, M.; Bovenga, F.; Carrière, V.; de Boer, J.F.; Dugardin, C.; Riveau, B.; Clavey, V.; Tailleux, A.; Moschetta, A.; Lasunción, M.A.; Groen, A.K.; Staels, B.; Lestavel, S.; Liver, X.; Liver, X. Receptor Regulates Triglyceride Absorption Through Intestinal Down-regulation of Scavenger Receptor Class B, Type 1. Gastroenterology, 2016, 150(3), 650-658.
[57]
Zhang, X.; Liu, J.; Su, W.; Wu, J.; Wang, C.; Kong, X.; Gustafsson, J.A.; Ding, J.; Ma, X.; Guan, Y. Liver X receptor activation increases hepatic fatty acid desaturation by the induction of SCD1 expression through an LXRα-SREBP1c-dependent mechanism. J. Diabetes, 2014, 6(3), 212-220.
[58]
Fu, Y.; Mukhamedova, N.; Ip, S.; D’Souza, W.; Henley, K.J.; DiTommaso, T.; Kesani, R.; Ditiatkovski, M.; Jones, L.; Lane, R.M.; Jennings, G.; Smyth, I.M.; Kile, B.T.; Sviridov, D. ABCA12 regulates ABCA1-dependent cholesterol efflux from macrophages and the development of atherosclerosis. Cell Metab., 2013, 18(2), 225-238.
[59]
Cruz-Garcia, L.; Schlegel, A. Lxr-driven enterocyte lipid droplet formation delays transport of ingested lipids. J. Lipid Res., 2014, 55(9), 1944-1958.
[60]
Efanov, A.M.; Sewing, S.; Bokvist, K.; Gromada, J. Liver X receptor activation stimulates insulin secretion via modulation of glucose and lipid metabolism in pancreatic beta-cells. Diabetes, 2004, 53(Suppl. 3), S75-S78.
[61]
Green, C.D.; Jump, D.B.; Olson, L.K. Elevated insulin secretion from liver X receptor-activated pancreatic beta-cells involves increased de novo lipid synthesis and triacylglyceride turnover. Endocrinology, 2009, 150(6), 2637-2645.
[62]
Meng, Z.X.; Yin, Y.; Lv, J.H.; Sha, M.; Lin, Y.; Gao, L.; Zhu, Y.X.; Sun, Y.J.; Han, X. Aberrant activation of liver X receptors impairs pancreatic beta cell function through upregulation of sterol regulatory element-binding protein 1c in mouse islets and rodent cell lines. Diabetologia, 2012, 55(6), 1733-1744.
[63]
Li, Y.; Jing, C.; Tang, X.; Chen, Y.; Han, X.; Zhu, Y. LXR activation causes G1/S arrest through inhibiting SKP2 expression in MIN6 pancreatic beta cells. Endocrine, 2016, 53(3), 689-700.
[64]
Steffensen, K.R.; Gustafsson, J.A. Putative metabolic effects of the Liver X Receptor (LXR). Diabetes, 2004, 53(Suppl. 1), S36-S42.
[65]
Pascual-García, M.; Rué, L.; León, T.; Julve, J.; Carbó, J.M.; Matalonga, J.; Auer, H.; Celada, A.; Escolà-Gil, J.C.; Steffensen, K.R.; Pérez-Navarro, E.; Valledor, A.F. Reciprocal negative cross-talk between Liver X Receptors (LXRs) and STAT1: effects on IFN-γ-induced inflammatory responses and LXR-dependent gene expression. J. Immunol., 2013, 190(12), 6520-6532.
[66]
Sun, X.; Haas, M.E.; Miao, J.; Mehta, A.; Graham, M.J.; Crooke, R.M.; Pais de Barros, J.P.; Wang, J.G.; Aikawa, M.; Masson, D.; Biddinger, S.B. Insulin dissociates the effects of liver x receptor on lipogenesis, endoplasmic reticulum stress, and inflammation. J. Biol. Chem., 2016, 291(3), 1115-1122.
[67]
Su, W.; Huang, S.Z.; Gao, M.; Kong, X.M.; Gustafsson, J.A.; Xu, S.J.; Wang, B.; Zheng, F.; Chen, L.H.; Wang, N.P.; Guan, Y.F.; Zhang, X.Y. Liver X receptor β increases aquaporin 2 protein level via a posttranscriptional mechanism in renal collecting ducts. Am. J. Physiol. Renal Physiol., 2017, 312(4), F619-F628.
[68]
Patel, M.; Wang, X.X.; Magomedova, L.; John, R.; Rasheed, A.; Santamaria, H.; Wang, W.; Tsai, R.; Qiu, L.; Orellana, A.; Advani, A.; Levi, M.; Cummins, C.L. Liver X receptors preserve renal glomerular integrity under normoglycaemia and in diabetes in mice. Diabetologia, 2014, 57(2), 435-446.
[69]
Hayashi, T.; Kotani, H.; Yamaguchi, T.; Taguchi, K.; Iida, M.; Ina, K.; Maeda, M.; Kuzuya, M.; Hattori, Y.; Ignarro, L.J. Endothelial cellular senescence is inhibited by liver X receptor activation with an additional mechanism for its atheroprotection in diabetes. Proc. Natl. Acad. Sci. USA, 2014, 111(3), 1168-1173.
[70]
Hammer, S.S.; Beli, E.; Kady, N.; Wang, Q.; Wood, K.; Lydic, T.A.; Malek, G.; Saban, D.R.; Wang, X.X.; Hazra, S.; Levi, M.; Busik, J.V.; Grant, M.B. The mechanism of diabetic retinopathy pathogenesis unifying key lipid regulators, sirtuin 1 and liver X receptor. EBioMedicine, 2017, 22, 181-190.
[71]
He, Q.; Pu, J.; Yuan, A.; Yao, T.; Ying, X.; Zhao, Y.; Xu, L.; Tong, H.; He, B. Liver X receptor agonist treatment attenuates cardiac dysfunction in type 2 diabetic db/db mice. Cardiovasc. Diabetol., 2014, 13, 149.
[72]
Cannon, M.V.; Silljé, H.H.; Sijbesma, J.W.; Khan, M.A.; Steffensen, K.R.; van Gilst, W.H.; de Boer, R.A. LXRα improves myocardial glucose tolerance and reduces cardiac hypertrophy in a mouse model of obesity-induced type 2 diabetes. Diabetologia, 2016, 59(3), 634-643.
[73]
Russell, D.W. Nuclear orphan receptors control cholesterol catabolism. Cell, 1999, 97(5), 539-542.
[74]
Otte, K.; Kranz, H.; Kober, I.; Thompson, P.; Hoefer, M.; Haubold, B.; Remmel, B.; Voss, H.; Kaiser, C.; Albers, M.; Cheruvallath, Z.; Jackson, D.; Casari, G.; Koegl, M.; Pääbo, S.; Mous, J.; Kremoser, C.; Deuschle, U. Identification of farnesoid X receptor beta as a novel mammalian nuclear receptor sensing lanosterol. Mol. Cell. Biol., 2003, 23(3), 864-872.
[75]
Chiang, J.Y.; Pathak, P.; Liu, H.; Donepudi, A.; Ferrell, J.; Boehme, S. Intestinal farnesoid X receptor and takeda G protein couple receptor 5 signaling in metabolic regulation. Dig. Dis., 2017, 35(3), 241-245.
[76]
Pathak, P.; Liu, H.; Boehme, S.; Xie, C.; Krausz, K.W.; Gonzalez, F.; Chiang, J.Y.L. 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.
[78]
Kliewer, S.A.; Mangelsdorf, D.J. Bile Acids as hormones: The FXR-FGF15/19 pathway. Dig. Dis., 2015, 33(3), 327-331.
[79]
Schmitt, J.; Kong, B.; Stieger, B.; Tschopp, O.; Schultze, S.M.; Rau, M.; Weber, A.; Müllhaupt, B.; Guo, G.L.; Geier, A. Protective effects of Farnesoid X Receptor (FXR) on hepatic lipid accumulation are mediated by hepatic FXR and independent of intestinal FGF15 signal. Liver Int., 2015, 35(4), 1133-1144.
[80]
Sonne, D.P.; van Nierop, F.S.; Kulik, W.; Soeters, M.R.; Vilsbøll, T.; Knop, F.K. Postprandial plasma concentrations of individual bile acids and FGF-19 in patients with type 2 diabetes. J. Clin. Endocrinol. Metab., 2016, 101(8), 3002-3009.
[81]
Zhang, J.; Li, H.; Zhou, H.; Fang, L.; Xu, J.; Yan, H.; Chen, S.; Song, Q.; Zhang, Y.; Xu, A.; Fang, Q.; Ye, Y.; Jia, W. Lowered fasting chenodeoxycholic acid correlated with the decrease of fibroblast growth factor 19 in Chinese subjects with impaired fasting glucose. Sci. Rep., 2017, 7(1), 6042.
[83]
Båvner, A.; Sanyal, S.; Gustafsson, J.A.; Treuter, E. Transcriptional corepression by SHP: molecular mechanisms and physiological consequences. Trends Endocrinol. Metab., 2005, 16(10), 478-488.
[84]
Del Bas, J.M.; Ricketts, M.L.; Vaqué, M.; Sala, E.; Quesada, H.; Ardevol, A.; Salvadó, M.J.; Blay, M.; Arola, L.; Moore, D.D.; Pujadas, G.; Fernandez-Larrea, J.; Bladé, C. Dietary procyanidins enhance transcriptional activity of bile acid-activated FXR in vitro and reduce triglyceridemia in vivo in a FXR-dependent manner. Mol. Nutr. Food Res., 2009, 53(7), 805-814.
[85]
Watanabe, M.; Houten, S.M.; Wang, L.; Moschetta, A.; Mangelsdorf, D.J.; Heyman, R.A.; Moore, D.D.; Auwerx, J. Bile acids lower triglyceride levels via a pathway involving FXR, SHP, and SREBP-1c. J. Clin. Invest., 2004, 113(10), 1408-1418.
[86]
Stroeve, J.H.; Brufau, G.; Stellaard, F.; Gonzalez, F.J.; Staels, B.; Kuipers, F. Intestinal FXR-mediated FGF15 production contributes to diurnal control of hepatic bile acid synthesis in mice. Lab. Invest., 2010, 90(10), 1457-1467.
[87]
Ma, K.; Saha, P.K.; Chan, L.; Moore, D.D. Farnesoid X receptor is essential for normal glucose homeostasis. J. Clin. Invest., 2006, 116(4), 1102-1109.
[88]
Kim, K.H.; Choi, S.; Zhou, Y.; Kim, E.Y.; Lee, J.M.; Saha, P.K.; Anakk, S.; Moore, D.D. Hepatic FXR/SHP axis modulates systemic glucose and fatty acid homeostasis in aged mice. Hepatology, 2017, 66(2), 498-509.
[89]
Akinrotimi, O.; Riessen, R.; VanDuyne, P.; Park, J.E.; Lee, Y.K.; Wong, L.J.; Zavacki, A.M.; Schoonjans, K.; Anakk, S. Small heterodimer partner deletion prevents hepatic steatosis and when combined with farnesoid X receptor loss protects against type 2 diabetes in mice. Hepatology, 2017, 66(6), 1854-1865.
[90]
Prawitt, J.; Abdelkarim, M.; Stroeve, J.H.; Popescu, I.; Duez, H.; Velagapudi, V.R.; Dumont, J.; Bouchaert, E.; van Dijk, T.H.; Lucas, A.; Dorchies, E.; Daoudi, M.; Lestavel, S.; Gonzalez, F.J.; Oresic, M.; Cariou, B.; Kuipers, F.; Caron, S.; Staels, B. Farnesoid X receptor deficiency improves glucose homeostasis in mouse models of obesity. Diabetes, 2011, 60(7), 1861-1871.
[91]
Zhang, Y.; Ge, X.; Heemstra, L.A.; Chen, W.D.; Xu, J.; Smith, J.L.; Ma, H.; Kasim, N.; Edwards, P.A.; Novak, C.M. Loss of FXR protects against diet-induced obesity and accelerates liver carcinogenesis in ob/ob mice. Mol. Endocrinol., 2012, 26(2), 272-280.
[92]
Zhang, Y.; Lee, F.Y.; Barrera, G.; Lee, H.; Vales, C.; Gonzalez, F.J.; Willson, T.M.; Edwards, P.A. Activation of the nuclear receptor FXR improves hyperglycemia and hyperlipidemia in diabetic mice. Proc. Natl. Acad. Sci. USA, 2006, 103(4), 1006-1011.
[93]
Cariou, B.; van Harmelen, K.; Duran-Sandoval, D.; van Dijk, T.H.; Grefhorst, A.; Abdelkarim, M.; Caron, S.; Torpier, G.; Fruchart, J.C.; Gonzalez, F.J.; Kuipers, F.; Staels, B. The farnesoid X receptor modulates adiposity and peripheral insulin sensitivity in mice. J. Biol. Chem., 2006, 281(16), 11039-11049.
[94]
Cipriani, S.; Mencarelli, A.; Palladino, G.; Fiorucci, S. FXR activation reverses insulin resistance and lipid abnormalities and protects against liver steatosis in Zucker (fa/fa) obese rats. J. Lipid Res., 2010, 51(4), 771-784.
[95]
Watanabe, M.; Horai, Y.; Houten, S.M.; 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(30), 26913-26920.
[96]
Zhang, Y.; Lee, F.Y.; Barrera, G.; Lee, H.; Vales, C.; Gonzalez, F.J.; Willson, T.M.; Edwards, P.A. Activation of the nuclear receptor FXR improves hyperglycemia and hyperlipidemia in diabetic mice. Proc. Natl. Acad. Sci. USA, 2006, 103(4), 1006-1011.
[97]
Potthoff, M.J.; Boney-Montoya, J.; Choi, M.; He, T.; Sunny, N.E.; Satapati, S.; Suino-Powell, K.; Xu, H.E.; Gerard, R.D.; Finck, B.N.; Burgess, S.C.; Mangelsdorf, D.J.; Kliewer, S.A. FGF15/19 regulates hepatic glucose metabolism by inhibiting the CREB-PGC-1α pathway. Cell Metab., 2011, 13(6), 729-738.
[98]
Shen, H.; Zhang, Y.; Ding, H.; Wang, X.; Chen, L.; Jiang, H.; Shen, X. Farnesoid X receptor induces GLUT4 expression through FXR response element in the GLUT4 promoter. Cell. Physiol. Biochem., 2008, 22(1-4), 1-14.
[99]
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.
[100]
Li, T.; Francl, J.M.; Boehme, S.; Ochoa, A.; Zhang, Y.; Klaassen, C.D.; Erickson, S.K.; Chiang, J.Y. Glucose and insulin induction of bile acid synthesis: mechanisms and implication in diabetes and obesity. J. Biol. Chem., 2012, 287(3), 1861-1873.
[101]
Düfer, M.; Hörth, K.; Wagner, R.; Schittenhelm, B.; Prowald, S.; Wagner, T.F.; Oberwinkler, J.; Lukowski, R.; Gonzalez, F.J.; 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(6), 1479-1489.
[102]
Trabelsi, M.S.; Daoudi, M.; Prawitt, J.; Ducastel, S.; Touche, V.; Sayin, S.I.; Perino, A.; Brighton, C.A.; 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, F.M.; 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.
[103]
Jiang, T.; Wang, X.X.; 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.
[104]
Wang, X.X.; Jiang, T.; Shen, Y.; Caldas, Y.; Miyazaki-Anzai, S.; Santamaria, H.; Urbanek, C.; Solis, N.; Scherzer, P.; Lewis, L.; Gonzalez, F.J.; Adorini, L.; Pruzanski, M.; Kopp, J.B.; Verlander, J.W.; Levi, M. Diabetic nephropathy is accelerated by farnesoid X receptor deficiency and inhibited by farnesoid X receptor activation in a type 1 diabetes model. Diabetes, 2010, 59(11), 2916-2927.
[105]
Glastras, S.J.; Wong, M.G.; Chen, H.; Zhang, J.; Zaky, A.; Pollock, C.A.; Saad, S. FXR expression is associated with dysregulated glucose and lipid levels in the offspring kidney induced by maternal obesity. Nutr. Metab. (Lond.), 2015, 12, 40.
[106]
Wang, X.X.; Wang, D.; Luo, Y.; Myakala, K.; Dobrinskikh, E.; Rosenberg, A.Z.; Levi, J.; Kopp, J.B.; Field, A.; Hill, A.; Lucia, S.; Qiu, L.; Jiang, T.; Peng, Y.; Orlicky, D.; Garcia, G.; Herman-Edelstein, M.; D’Agati, V.; Henriksen, K.; Adorini, L.; Pruzanski, M.; Xie, C.; Krausz, K.W.; Gonzalez, F.J.; Ranjit, S.; Dvornikov, A.; Gratton, E.; Levi, M. FXR/TGR5 Dual Agonist Prevents Progression of Nephropathy in Diabetes and Obesity. J. Am. Soc. Nephrol., 2018, 29(1), 118-137.
[107]
Timsit, Y.E.; Negishi, M. Coordinated regulation of nuclear receptor CAR by CCRP/DNAJC7, HSP70 and the ubiquitin-proteasome system. PLoS One, 2014, 9(5), e96092.
[108]
Dash, A.K.; Yende, A.S.; Jaiswal, B.; Tyagi, R.K. Heterodimerization of Retinoid X Receptor with Xenobiotic Receptor partners occurs in the cytoplasmic compartment: Mechanistic insights of events in living cells. Exp. Cell Res., 2017, 360(2), 337-346.
[109]
Hassani-Nezhad-Gashti, F.; Rysä, J.; Kummu, O.; Näpänkangas, J.; Buler, M.; Karpale, M.; Hukkanen, J.; Hakkola, J. Activation of nuclear receptor PXR impairs glucose tolerance and dysregulates GLUT2 expression and subcellular localization in liver. Biochem. Pharmacol., 2018, 148, 253-264.
[110]
Ling, Z.; Shu, N.; Xu, P.; Wang, F.; Zhong, Z.; Sun, B.; Li, F.; Zhang, M.; Zhao, K.; Tang, X.; Wang, Z.; Zhu, L.; Liu, L.; Liu, X. Involvement of pregnane X receptor in the impaired glucose utilization induced by atorvastatin in hepatocytes. Biochem. Pharmacol., 2016, 100, 98-111.
[111]
Gotoh, S.; Negishi, M. Statin-activated nuclear receptor PXR promotes SGK2 dephosphorylation by scaffolding PP2C to induce hepatic gluconeogenesis. Sci. Rep., 2015, 5, 14076.
[112]
Rysä, J.; Buler, M.; Savolainen, M.J.; Ruskoaho, H.; Hakkola, J.; Hukkanen, J. Pregnane X receptor agonists impair postprandial glucose tolerance. Clin. Pharmacol. Ther., 2013, 93(6), 556-563.
[113]
Hukkanen, J.; Rysa, J.; Makela, K.A.; Herzig, K.H.; Hakkola, J.; Savolainen, M.J. The effect of pregnane X receptor agonists on postprandial incretin hormone secretion in rats and humans. J. Physiol. Pharmacol., 2015, 66(6), 831-839.
[114]
He, J.; Gao, J.; Xu, M.; Ren, S.; Stefanovic-Racic, M.; O’Doherty, R.M.; Xie, W. PXR ablation alleviates diet-induced and genetic obesity and insulin resistance in mice. Diabetes, 2013, 62(6), 1876-1887.
[115]
Gao, J.; Yan, J.; Xu, M.; Ren, S.; Xie, W. CAR Suppresses Hepatic Gluconeogenesis by Facilitating the Ubiquitination and Degradation of PGC1α. Mol. Endocrinol., 2015, 29(11), 1558-1570.
[116]
Masuyama, H.; Mitsui, T.; Maki, J.; Tani, K.; Nakamura, K.; Hiramatsu, Y. Dimethylesculetin ameliorates maternal glucose intolerance and fetal overgrowth in high-fat diet-fed pregnant mice via constitutive androstane receptor. Mol. Cell. Biochem., 2016, 419(1-2), 185-192.
[117]
Yarushkin, A.A.; Kazantseva, Y.A.; Prokopyeva, E.A.; Markova, D.N.; Pustylnyak, Y.A.; Pustylnyak, V.O. Constitutive androstane receptor activation evokes the expression of glycolytic genes. Biochem. Biophys. Res. Commun., 2016, 478(3), 1099-1105.
[118]
Paul, D.S.; Teschendorff, A.E.; Dang, M.A.; Lowe, R.; Hawa, M.I.; Ecker, S.; Beyan, H.; Cunningham, S.; Fouts, A.R.; Ramelius, A.; Burden, F.; Farrow, S.; Rowlston, S.; Rehnstrom, K.; Frontini, M.; Downes, K.; Busche, S.; Cheung, W.A.; Ge, B.; Simon, M.M.; Bujold, D.; Kwan, T.; Bourque, G.; Datta, A.; Lowy, E.; Clarke, L.; Flicek, P.; Libertini, E.; Heath, S.; Gut, M.; Gut, I.G.; Ouwehand, W.H.; Pastinen, T.; Soranzo, N.; Hofer, S.E.; Karges, B.; Meissner, T.; Boehm, B.O.; Cilio, C.; Elding Larsson, H.; Lernmark, Å.; Steck, A.K.; Rakyan, V.K.; Beck, S.; Leslie, R.D. Increased DNA methylation variability in type 1 diabetes across three immune effector cell types. Nat. Commun., 2016, 7, 13555.
Related Books
Localized Micro/Nanocarriers for Programmed and On-Demand Controlled Drug Release
Mixed Polymeric Micelles for Osteosarcoma Therapy: Development and Characterization
A Comprehensive Text Book on Self-emulsifying Drug Delivery Systems
Nanomaterials: Evolution and Advancement towards Therapeutic Drug Delivery (Part II)
Nanomaterials: Evolution and Advancement Towards Therapeutic Drug Delivery (Part I)
Article Metrics
64
6
1