Nuclear Receptors as Therapeutic Targets in Liver Disease: Are We There Yet?

Annual Review of Pharmacology and Toxicology

Volumn 56, Issue , 2016, Pages 605-626

  Rudraiah, Swetha ^a   Zhang, Xi ^a   Wang, Li ^a,b,c  

^a UNIVERSITY OF CONNECTICUT   (United States)

^b VA CONNECTICUT HEALTHCARE SYSTEM   (United States)

^c YALE UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

Cholestatic liver disease; Drug induced liver injury; Hepatocellular cancer; Liver inflammation and fibrosis; Nonalcoholic fatty liver; Viral hepatitis infection

Indexed keywords

CELL NUCLEUS RECEPTOR; CONSTITUTIVE ANDROSTANE RECEPTOR; FARNESOID X RECEPTOR; GLUCOSE; LIPID; LIVER X RECEPTOR; LONG UNTRANSLATED RNA; MICRORNA; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR; PREGNANE X RECEPTOR; RETINOID X RECEPTOR; SMALL UNTRANSLATED RNA; TRANSCRIPTION FACTOR; VITAMIN D RECEPTOR; XENOBIOTIC AGENT; CELL RECEPTOR; LIGAND;

ARTICLE; CELL DIFFERENTIATION; CELL MATURATION; CELL METABOLISM; CELL PROLIFERATION; GLUCOSE METABOLISM; HUMAN; INTRAHEPATIC CHOLESTASIS; LIPID METABOLISM; LIVER CELL CARCINOMA; LIVER DISEASE; LIVER FIBROSIS; LIVER REGENERATION; NONALCOHOLIC FATTY LIVER; NONHUMAN; PATHOPHYSIOLOGY; PRIORITY JOURNAL; TOXIC HEPATITIS; VIRUS HEPATITIS; ANIMAL; LIVER; METABOLISM;

ANIMALS; HUMANS; LIGANDS; LIVER; LIVER DISEASES; RECEPTORS, CYTOPLASMIC AND NUCLEAR;

EID: 84954154759     PISSN: 03621642     EISSN: 15454304     Source Type: Book Series    
DOI: 10.1146/annurev-pharmtox-010715-103209     Document Type: Article

References (146)

1. Arrese M, Karpen SJ. 2010. Nuclear receptors, inflammation, and liver disease: insights for cholestatic and fatty liver diseases. Clin. Pharmacol. Ther. 87(4):473-78
2. Sladek FM. 2003. Nuclear receptors as drug targets: new developments in coregulators, orphan receptors and major therapeutic areas. Expert Opin. Ther. Targets 7(5):679-84
3. Evans R. 2004. A transcriptional basis for physiology. Nat. Med. 10(10):1022-26
4. Trauner M, Halilbasic E. 2011. Nuclear receptors as new perspective for the management of liver diseases. Gastroenterology 140(4):1120-1125. e1-12
5. Wagner M, Zollner G, Trauner M. 2011. Nuclear receptors in liver disease. Hepatology 53(3):1023-34
6. Zhang Y, Hagedorn CH, Wang L. 2011. Role of nuclear receptor SHP in metabolism and cancer. Biochim. Biophys. Acta 1812(8):893-908
7. Sonoda J, Pei L, Evans RM. 2008. Nuclear receptors: decoding metabolic disease. FEBS Lett. 582(1):2-9
8. Knight BL,Hebbachi A,HautonD, Brown AM,Wiggins D, et al. 2005. A role for PPAR-in the control of SREBP activity and lipid synthesis in the liver. Biochem. J. 389(Pt. 2):413-21
9. Schadinger SE, Bucher NL, Schreiber BM, Farmer SR. 2005. PPAR-2 regulates lipogenesis and lipid accumulation in steatotic hepatocytes. Am. J. Physiol. Endocrinol. Metab. 288(6):E1195-205
10. Shen LL, Liu H, Peng J, Gan L, Zhang Q, et al. 2011. Effects of farnesoid X receptor on the expression of the fatty acid synthetase and hepatic lipase. Mol. Biol. Rep. 38(1):553-59
11. Schultz JR, Tu H, Luk A, Repa JJ, Medina JC, et al. 2000. Role of LXRs in control of lipogenesis. Genes Dev. 14(22):2831-38
12. Bechmann LP, Hannivoort RA, Gerken G, Hotamisligil GS, Trauner M, Canbay A. 2012. The interaction of hepatic lipid and glucose metabolism in liver diseases. J. Hepatol. 56(4):952-64
13. Wierzbicki M, Chabowski A, Zendzian-Piotrowska M, Gorski J. 2009. Differential effects of in vivo PPAR? and activation on fatty acid transport proteins expression and lipid content in rat liver. J. Physiol. Pharmacol. 60(1):99-106
14. Ge F, Zhou S, Hu C, Lobdell H 4th, Berk PD. 2010. Insulin-and leptin-regulated fatty acid uptake plays a key causal role in hepatic steatosis in mice with intact leptin signaling but not in ob/ob or db/db mice. Am. J. Physiol. Gastrointest. Liver Physiol. 299(4):G855-66
15. Huang J, Iqbal J, Saha PK, Liu J, Chan L, et al. 2007. Molecular characterization of the role of orphan receptor small heterodimer partner in development of fatty liver. Hepatology 46(1):147-57
16. Zhang Y, Wang L. 2011. Nuclear receptor small heterodimer partner in apoptosis signaling and liver cancer. Cancers 3(1):198-212
17. Leturque A, Brot-Laroche E, Le Gall M. 2009. GLUT2 mutations, translocation, and receptor function in diet sugar managing. Am. J. Physiol. Endocrinol. Metab. 296(5):E985-92
18. Agius L. 2008. Glucokinase and molecular aspects of liver glycogen metabolism. Biochem. J. 414(1):1-18
19. Oosterveer MH, Schoonjans K. 2014. Hepatic glucose sensing and integrative pathways in the liver. Cell Mol. Life Sci. 71(8):1453-67
20. Wang L, Liu J, Saha P, Huang J, Chan L, et al. 2005. The orphan nuclear receptor SHP regulates PGC-1-expression and energy production in brown adipocytes. Cell Metab. 2(4):227-38
21. Stayrook KR, Bramlett KS, Savkur RS, Ficorilli J, Cook T, et al. 2005. Regulation of carbohydrate metabolism by the farnesoid X receptor. Endocrinology 146(3):984-91
22. Puigserver P, Rhee J, Donovan J,Walkey CJ, Yoon JC, et al. 2003. Insulin-regulated hepatic gluconeogenesis through FOXO1-PGC-1-interaction. Nature 423(6939):550-55
23. Kim TH, Kim H, Park JM, Im SS, Bae Js, et al. 2009. Interrelationship between liver X receptor, sterol regulatory element-binding protein-1c, peroxisome proliferator-activated receptor, and small heterodimer partner in the transcriptional regulation of glucokinase gene expression in liver. J. Biol. Chem. 284(22):15071-83
24. Borgius LJ, Steffensen KR, Gustafsson JA, Treuter E. 2002. Glucocorticoid signaling is perturbed by the atypical orphan receptor and corepressor SHP. J. Biol. Chem. 277(51):49761-66
25. Park MJ, Kong HJ, Kim HY, Kim HH, Kim JH, Cheong JH. 2007. Transcriptional repression of the gluconeogenic gene PEPCK by the orphan nuclear receptor SHP through inhibitory interaction with C/EBP. Biochem. J. 402(3):567-74
26. Ma Y, Huang Y, Yan L, Gao M, Liu D. 2013. Synthetic FXR agonist GW4064 prevents diet-induced hepatic steatosis and insulin resistance. Pharm. Res. 30(5):1447-57
27. Gege C, Kinzel O, Steeneck C, Schulz A, Kremoser C. 2014. Knocking on FXR's door: The "hammerhead"-structure series of FXR agonists-amphiphilic isoxazoles with potent in vitro and in vivo activities. Curr. Top. Med. Chem. 14(19):2143-58
28. GaoM, Liu D. 2013. Resveratrol suppresses T0901317-induced hepatic fat accumulation inmice. AAPS J. 15(3):744-52
29. Kay HY, Kim WD, Hwang SJ, ChoiHS, Gilroy RK, et al. 2011. Nrf2 inhibits LXR-dependent hepatic lipogenesis by competing with FXR for acetylase binding. Antioxid. Redox Signal. 15(8):2135-46
30. Gao M, Liu D. 2013. The liver X receptor agonist T0901317 protects mice from high fat diet-induced obesity and insulin resistance. AAPS J. 15(1):258-66
31. Rogue A, Anthérieu S, Vluggens A, Umbdenstock T, Claude N, et al. 2014. PPAR agonists reduce steatosis in oleic acid-overloaded HepaRG cells. Toxicol. Appl. Pharmacol. 276(1):73-81
32. Goto T, Kim Y-I, FunakoshiK, Teraminami A,UemuraT, et al. 2011. Farnesol, an isoprenoid, improves metabolic abnormalities in mice via both PPAR-dependent and-independent pathways. Am. J. Physiol. Endocrinol. Metab. 301(5):E1022-32
33. Chang E, Park CY, Park SW. 2013. Role of thiazolidinediones, insulin sensitizers, in non-alcoholic fatty liver disease. J. Diabetes Investig. 4(6):517-24
34. Hajiaghamohammadi AA, Ziaee A, Oveisi S, Masroor H. 2012. Effects of metformin, pioglitazone, and silymarin treatment on non-alcoholic fatty liver disease: A randomized controlled pilot study. Hepat. Mon. 12(8):e6099
35. Jin SM, Park CY, Cho YM, Ku BJ, Ahn CW, et al. 2015. Lobeglitazone and pioglitazone as addons to metformin for patients with type 2 diabetes: A 24-week, multicentre, randomized, double-blind, parallel-group, active-controlled, phase III clinical trial with a 28-week extension. Diabetes Obes. Metab. 17(6):599-602
36. Smalling RL, Delker DA, Zhang Y, Nieto N, McGuiness MS, et al. 2013. Genome-wide transcriptome analysis identifies novel gene signatures implicated in human chronic liver disease. Am. J. Physiol. Gastrointest. Liver Physiol. 305(5):G364-74
37. Benet M, Guzmán C, Pisonero-Vaquero S, Garca-Mediavilla MV, Sánchez-Campos S, et al. 2015. Repression of the nuclear receptor small heterodimer partner by steatotic drugs and in advanced nonalcoholic fatty liver disease. Mol. Pharmacol. 87(4):582-94
38. Tabbi-Anneni I, Cooksey R, Gunda V, Liu S,Mueller A, et al. 2010. Overexpression of nuclear receptor SHP in adipose tissues affects diet-induced obesity and adaptive thermogenesis. Am. J. Physiol. Endocrinol. Metab. 298(5):E961-70
39. Pan X, Zhang Y, Wang L, Hussain MM. 2010. Diurnal regulation of MTP and plasma triglyceride by CLOCK is mediated by SHP. Cell Metab. 12(2):174-86
40. Lee SM, Zhang Y, Tsuchiya H, Smalling R, Jetten AM, Wang L. 2015. Small heterodimer partner/neuronal PAS domain protein 2 axis regulates the oscillation of liver lipid metabolism. Hepatology 61(2):497-505
41. Tsuchiya H, da CostaKA, Lee S, Renga B, Jaeschke H, et al. 2015. Interactions between nuclear receptor SHP and FOXA1 maintain oscillatory homocysteine homeostasis in mice. Gastroenterology 148(5):1012-23. e14
42. Miyata M, Sakaida Y, Matsuzawa H, Yoshinari K, Yamazoe Y. 2011. Fibroblast growth factor 19 treatment ameliorates disruption of hepatic lipid metabolism in farnesoid X receptor (Fxr)-null mice. Biol. Pharm. Bull. 34(12):1885-89
43. Tilg H, Moschen AR. 2010. Evolution of inflammation in nonalcoholic fatty liver disease: The multiple parallel hits hypothesis. Hepatology 52(5):1836-46
44. Wang YD, Chen WD,WangM, YuD, Forman BM, HuangW. 2008. Farnesoid X receptor antagonizes nuclear factorB in hepatic inflammatory response. Hepatology 48(5):1632-43
45. Wagner M, Zollner G, TraunerM. 2008. Nuclear bile acid receptor farnesoid X receptor meets nuclear factor-B: new insights into hepatic inflammation. Hepatology 48(5):1383-86
46. Ogawa S, Lozach J, Benner C, Pascual G, Tangirala RK, et al. 2005. Molecular determinants of crosstalk between nuclear receptors and toll-like receptors. Cell 122(5):707-21
47. Pawlak M, Baugé E, Bourguet W, De Bosscher K, Lalloyer F, et al. 2014. The transrepressive activity of peroxisome proliferator-activated receptor alpha is necessary and sufficient to prevent liver fibrosis in mice. Hepatology 60(5):1593-606
48. Huang W, Glass CK. 2010. Nuclear receptors and inflammation control: molecular mechanisms and pathophysiological relevance. Arterioscler. Thromb. Vasc. Biol. 30(8):1542-49
49. Zelcer N, Tontonoz P. 2006. Liver X receptors as integrators of metabolic and inflammatory signaling. J. Clin. Investig. 116(3):607-14
50. Lee YA, Wallace MC, Friedman SL. 2015. Pathobiology of liver fibrosis: A translational success story. Gut 64(5):830-41
51. Fickert P, Fuchsbichler A,Moustafa T, Wagner M, Zollner G, et al. 2009. Farnesoid X receptor critically determines the fibrotic response in mice but is expressed to a low extent in human hepatic stellate cells and periductal myofibroblasts. Am. J. Pathol. 175(6):2392-405
52. Sharvit E, Abramovitch S, Reif S, Bruck R. 2013. Amplified inhibition of stellate cell activation pathways by PPAR-, RAR and RXR agonists. PLOS ONE 8(10):e76541
53. Ding N, Yu RT, Subramaniam N, Sherman MH, Wilson C, et al. 2013. A vitamin D receptor/SMAD genomic circuit gates hepatic fibrotic response. Cell 153(3):601-13
54. Li T, Eheim AL, Klein S, Uschner FE, Smith AC, et al. 2014. Novel role of nuclear receptor Rev-erb in hepatic stellate cell activation: potential therapeutic target for liver injury. Hepatology 59(6):2383-96
55. Beaven SW, Wroblewski K, Wang J, Hong C, Bensinger S, et al. 2011. Liver X receptor signaling is a determinant of stellate cell activation and susceptibility to fibrotic liver disease. Gastroenterology 140(3):1052-62
56. Zhang S,Wang J, Liu Q, HarnishDC. 2009. Farnesoid X receptor agonistWAY-362450 attenuates liver inflammation and fibrosis in murine model of non-alcoholic steatohepatitis. J. Hepatol. 51(2):380-88
57. Mudaliar S, Henry RR, Sanyal AJ, Morrow L, Marschall HU, et al. 2013. Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease. Gastroenterology 145(3):574-82. e1
58. Fiorucci S, Cipriani S, Mencaarelli A, Baldelli F, Bifulco G, Zampella A. 2011. Farnesoid X receptor agonist for the treatment of liver andmetabolic disorders: focus on 6-ethyl-CDCA. Mini Rev. Med. Chem. 11(9):753-62
59. Hirschfield GM,Mason A, Luketic V, Lindor K, Gordon SC, et al. 2014. Efficacy of obeticholic acid in patients with primary biliary cirrhosis and inadequate response to ursodeoxycholic acid. Gastroenterology 148(4):751-61. e8
60. Ahn SB, Jang K, Jun DW, Lee BH, Shin KJ. 2014. Expression of liver X receptor correlates with intrahepatic inflammation and fibrosis in patients with nonalcoholic fatty liver disease. Dig. Dis. Sci. 59(12):2975-82
61. Liu Q,Wang CY, Liu Z, Ma XS, He YH, et al. 2014. Hydroxysafflor yellow A suppresses liver fibrosis induced by carbon tetrachloride with high-fat diet by regulating PPAR-/p38 MAPK signaling. Pharm. Biol. 52(9):1085-93
62. AttiaYM, ElalkamyEF,HammamOA,MahmoudSS, El-KhatibAS. 2013. Telmisartan, anAT1receptor blocker and a PPAR activator, alleviates liver fibrosis induced experimentally by Schistosoma mansoni infection. Parasites Vectors 6:199
63. Baghdasaryan A, Claudel T, Kosters A, Gumhold J, Silbert D, et al. 2010. Curcumin improves sclerosing cholangitis in Mdr2/mice by inhibition of cholangiocyte inflammatory response and portal myofibroblast proliferation. Gut 59(4):521-30
64. Honda A, Ikegami T, Nakamuta M, Miyazaki T, Iwamoto J, et al. 2013. Anticholestatic effects of bezafibrate in patients with primary biliary cirrhosis treated with ursodeoxycholic acid. Hepatology 57(5):1931-41
65. Galli A, Crabb DW, Ceni E, Salzano R, Mello T, et al. 2002. Antidiabetic thiazolidinediones inhibit collagen synthesis and hepatic stellate cell activation in vivo and in vitro. Gastroenterology 122(7):1924-40
66. Cariou B, Zär Y, Staels B, Bruckert E. 2011. Effects of the new dual PPAR/agonist GFT505 on lipid and glucose homeostasis in abdominally obese patients with combined dyslipidemia or impaired glucose metabolism. Diabetes Care 34(9):2008-14
67. Hellemans K, Grinko I, Rombouts K, SchuppanD,Geerts A. 1999. All-trans and 9-cis retinoic acid alter rat hepatic stellate cell phenotype differentially. Gut 45(1):134-42
68. Bruck R,Weiss S, Aeed H, PinesM, Halpern Z, Zvibel I. 2009. Additive inhibitory effect of experimentally induced hepatic cirrhosis by agonists of peroxisome proliferator activator receptor and retinoic acid receptor. Dig. Dis. Sci. 54(2):292-99
69. Hellemans K, Verbuyst P, Quartier E, Schuit F, Rombouts K, et al. 2004. Differential modulation of rat hepatic stellate phenotype by natural and synthetic retinoids. Hepatology 39(1):97-108
70. Ogura M, Nishida S, IshizawaM, Sakurai K, Shimizu M, et al. 2009. VitaminD3 modulates the expression of bile acid regulatory genes and represses inflammation in bile duct-ligated mice. J. Pharmacol. Exp. Ther. 328(2):564-70
71. Abramovitch S, Dahan-Bachar L, Sharvit E, Weisman Y, Ben Tov A, et al. 2011. Vitamin D inhibits proliferation and profibrotic marker expression in hepatic stellate cells and decreases thioacetamideinduced liver fibrosis in rats. Gut 60(12):1728-37
72. Bjornsson E, Angulo P. 2007. Hepatitis C and steatosis. Arch. Med. Res. 38(6):621-27
73. Kim K, Kim KH, Kim HH, Cheong J. 2008. Hepatitis B virus X protein induces lipogenic transcription factor SREBP1 and fatty acid synthase through the activation of nuclear receptor LXR. Biochem. J. 416(2):219-30
74. Garcia-Mediavilla MV, Pisonero-Vaquero S, Lima-Cabello E, Benedicto I,Majano PL, et al. 2012. Liver Xreceptor-mediated regulation of lipogenesis by core andNS5A proteins contributes to HCV-induced liver steatosis and HCV replication. Lab. Investig. 92(8):1191-202
75. Shlomai A, Paran N, Shaul Y. 2006. PGC-1 controls hepatitis B virus through nutritional signals. PNAS 103(43):16003-8
76. Chhatwal P, Bankwitz D, Gentzsch J, Frentzen A, Schult P, et al. 2012. Bile acids specifically increase hepatitis C virus RNA-replication. PLOS ONE 7(4):e36029
77. KimHY,ChoHK,ChoiYH, LeeKS, Cheong J. 2010. Bile acids increase hepatitisBvirus gene expression and inhibit interferon-activity. FEBS J. 277(13):2791-802
78. Wakui Y, Inoue J, Ueno Y, Fukushima K, Kondo Y, et al. 2010. Inhibitory effect on hepatitis B virus in vitro by a peroxisome proliferator-activated receptor-ligand, rosiglitazone. Biochem. Biophys. Res. Commun. 396(2):508-14
79. Khattab M, Emad M, Abdelaleem A, Eslam M, Atef R, et al. 2010. Pioglitazone improves virological response to peginterferon 2b/ribavirin combination therapy in hepatitis C genotype 4 patients with insulin resistance. Liver Int. 30(3):447-54
80. Knop V, Bergk A, Schlosser B,Thieringer J, van Bömmel F, et al. 2013. Bezafibratemaintenance therapy in patients with advanced chronic hepatitis C. Eur. J. Gastroenterol. Hepatol. 25(5):594-600
81. Halilbasic E, Baghdasaryan A, Trauner M. 2013. Nuclear receptors as drug targets in cholestatic liver diseases. Clin. Liver Dis. 17(2):161-89
82. Baghdasaryan A, Chiba P, Trauner M. 2014. Clinical application of transcriptional activators of bile salt transporters. Mol. Aspects Med. 37:57-76
83. Strautnieks SS, Bull LN, Knisely AS, Kocoshis SA, Dahl N, et al. 1998. A gene encoding a liver-specific ABC transporter is mutated in progressive familial intrahepatic cholestasis. Nat. Genet. 20(3):233-38
84. Van Mil SW, Milona A, Dixon PH, Mullenbach R, Geenes VL, et al. 2007. Functional variants of the central bile acid sensor FXR identified in intrahepatic cholestasis of pregnancy. Gastroenterology 133(2):507-16
85. Bertolotti M, Gabbi C, Anzivino C, Mitro N, Godio C, et al. 2006. Decreased hepatic expression of PPAR-coactivator-1 in cholesterol cholelithiasis. Eur. J. Clin. Investig. 36(3):170-75
86. Lu TT, Makishima M, Repa JJ, Schoonjans K, Kerr TA, et al. 2000. Molecular basis for feedback regulation of bile acid synthesis by nuclear receptors. Mol. Cell 6(3):507-15
87. Wang L, Lee YK, Bundman D, Han Y, Thevananther S, et al. 2002. Redundant pathways for negative feedback regulation of bile acid production. Dev. Cell 2(6):721-31
88. Wang L, Han Y, Kim CS, Lee YK,Moore DD. 2003. Resistance of SHP-null mice to bile acid-induced liver damage. J. Biol. Chem. 278(45):44475-81
89. InagakiT,ChoiM,Moschetta A, Peng L, Cummins CL, et al. 2005. Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis. Cell Metab. 2(4):217-25
90. Castano G, Burgueño A, Fernández GT, Pirola CJ, Sookoian S. 2010. The influence of common gene variants of the xenobiotic receptor (PXR) in genetic susceptibility to intrahepatic cholestasis of pregnancy. Aliment. Pharmacol. Ther. 31(5):583-92
91. Karlsen TH, Lie BA, Frey FK, Thorsby E, Broomé U, et al. 2006. Polymorphisms in the steroid and xenobiotic receptor gene influence survival in primary sclerosing cholangitis. Gastroenterology 131(3):781-87
92. Chen HL, Liu YJ, Chen HL, Wu SH, Ni YH, et al. 2008. Expression of hepatocyte transporters and nuclear receptors in children with early and late-stage biliary atresia. Pediatr. Res. 63(6):667-73
93. Zhang Y, Xu N, Xu J, Kong B, Copple B, et al. 2014. E2F1 is a novel fibrogenic gene that regulates cholestatic liver fibrosis through the Egr-1/SHP/EID1 network. Hepatology 60(3):919-30
94. Zhang Y, Bonzo JA, Gonzalez FJ, Wang L. 2011. Diurnal regulation of the early growth response 1 (Egr-1) protein expression by hepatocyte nuclear factor 4 (HNF4) and small heterodimer partner (SHP) cross-talk in liver fibrosis. J. Biol. Chem. 286(34):29635-43
95. Baghdasaryan A, Claudel T, Gumhold J, Silbert D, Adorini L, et al. 2011. Dual farnesoid X receptor/TGR5 agonist INT-767 reduces liver injury in the Mdr2/(Abcb4/) mouse cholangiopathy model by promoting biliary output. Hepatology 54(4):1303-12
96. Wagner M, Halibasic E, Marschall HU, Zollner G, Fickert P, et al. 2005. CAR and PXR agonists stimulate hepatic bile acid and bilirubin detoxification and elimination pathways in mice. Hepatology 42(2):420-30
97. Stojakovic T, Putz-Bankuti C, Fauler G, Scharnagl H, Wagner M, et al. 2007. Atorvastatin in patients with primary biliary cirrhosis and incomplete biochemical response to ursodeoxycholic acid. Hepatology 46(3):776-84
98. Huang W, Zhang J, Moore DD. 2004. A traditional herbal medicine enhances bilirubin clearance by activating the nuclear receptor CAR. J. Clin. Investig. 113(1):137-43
99. RengaB,Migliorati M, Mencarelli A, Cipriani S,D'Amore C, et al. 2011. FarnesoidXreceptor suppresses constitutive androstane receptor activity at the multidrug resistance protein-4 promoter. Biochim. Biophys. Acta 1809(3):157-65
100. Huang W, Ma K, Zhang J, Qatanani M, Cuvillier J, et al. 2006. Nuclear receptor-dependent bile acid signaling is required for normal liver regeneration. Science 312(5771):233-36
101. Kim I, Morimura K, Shah Y, Yang Q,Ward JM, Gonzalez FJ. 2007. Spontaneous hepatocarcinogenesis in farnesoid X receptor-null mice. Carcinogenesis 28(5):940-46
102. He N, Park K, Zhang Y, Huang J, Lu S, Wang L. 2008. Epigenetic inhibition of nuclear receptor small heterodimer partner is associated with and regulates hepatocellular carcinoma growth. Gastroenterology 134(3):793-802
103. Zhang Y, Soto J, Park K, Viswanath G, Kuwada S, et al. 2010. Nuclear receptor SHP, a death receptor that targets mitochondria, induces apoptosis and inhibits tumor growth. Mol. Cell. Biol. 30(6):1341-56
104. Zhang Y, Wang L. 2013. Characterization of the mitochondrial localization of the nuclear receptor SHP and regulation of its subcellular distribution by interaction with Bcl2 and HNF4. PLOS ONE 8(7):e68491
105. Lee J, Padhye A, Shama A, Song G, Miao J, et al. 2010. A pathway involving farnesoid X receptor and small heterodimer partner positively regulates hepatic sirtuin 1 levels via microRNA-34a inhibition. J. Biol. Chem. 285(17):12604-11
106. Zhang Y, Xu P, Park K, Choi Y, Moore DD, Wang L. 2008. Orphan receptor small heterodimer partner suppresses tumorigenesis by modulating cyclin D1 expression and cellular proliferation. Hepatology 48(1):289-98
107. Zhang Y,Wang L. 2011. Nuclear receptor SHP inhibition of Dnmt1 expression via ERR. FEBS Lett. 585(9):1269-75
108. Zhang Y, Andrews GK, Wang L. 2012. Zinc-induced Dnmt1 expression involves antagonism between MTF-1 and nuclear receptor SHP. Nucleic Acids Res. 40(11):4850-60
109. Yang Z, Zhang Y, Kemper JK, Wang L. 2012. Cross-regulation of protein stability by p53 and nuclear receptor SHP. PLOS ONE 7(6):e39789
110. Yang Z, Wang L. 2012. An autoregulatory feedback loop between Mdm2 and SHP that fine tunesMdm2 and SHP stability. FEBS Lett. 586(8):1135-40
111. Yang Z, Zhang Y,Wang L. 2012. Mdm2 is a novel activator of ApoCIII promoter which is antagonized by p53 and SHP inhibition. Biochem. Biophys. Res. Commun. 417(2):744-46
112. Costa RH, Kalinichenko VV, Tan Y, Wang IC. 2005. The CAR nuclear receptor and hepatocyte proliferation. Hepatology 42(5):1004-8
113. Pascussi JM, Robert A, Moreau A, Ramos J, Bioulac-Sage P, et al. 2007. Differential regulation of constitutive androstane receptor expression by hepatocyte nuclear factor4-isoforms. Hepatology 45(5):1146-53
114. Phillips JM, Yamamoto Y, Negishi M, Maronpot RR, Goodman JI. 2007. Orphan nuclear receptor constitutive active/androstane receptor-mediated alterations in DNA methylation during phenobarbital promotion of liver tumorigenesis. Toxicol. Sci. 96(1):72-82
115. Dong B, Lee J-S, Park Y-Y, Yang F, Xu G, et al. 2015. Activating CAR and catenin induces uncontrolled liver growth and tumorigenesis. Nat. Commun. 6:5944
116. Misra P, Reddy JK. 2014. Peroxisome proliferator-activated receptor-activation and excess energy burning in hepatocarcinogenesis. Biochimie 98:63-74
117. Dai G, He L, Bu P, Wan YJ. 2008. Pregnane X receptor is essential for normal progression of liver regeneration. Hepatology 47(4):1277-87
118. Venteclef N, Ferre P. 2014. Liver X receptor: from metabolism to cancer. Biochem. J. 459(2):e1-3
119. Vaquero J, Briz O, Herraez E, Muntané J, Marin JJ. 2013. Activation of the nuclear receptor FXR enhances hepatocyte chemoprotection and liver tumor chemoresistance against genotoxic compounds. Biochim. Biophys. Acta 1833(10):2212-19
120. Zhang Y,GongW,Dai S, HuangG, Shen X, et al. 2012. Downregulation of human farnesoid X receptor by miR-421 promotes proliferation and migration of hepatocellular carcinoma cells. Mol. Cancer Res. 10(4):516-22
121. Zhong XY, Yu JH, Zhang WG, Wang ZD, Dong Q, et al. 2012. MicroRNA-421 functions as an oncogenic miRNA in biliary tract cancer through down-regulating farnesoid X receptor expression. Gene 493(1):44-51
122. Zabielski P, Blachnio-Zabielska A, Baranowski M, Zendzian-Piotrowska M, Gorski J. 2010. Activation of PPAR-by bezafibrate negatively affects de novo synthesis of sphingolipids in regenerating rat liver. Prostaglandins Other Lipid Mediat. 93(3-4):120-25
123. Wang F, Zhao SZ, Zhang MY, Ma YL, Zhang P Qin HL. 2013. Decreased risk of liver cancer with thiazolidinediones therapy in patients with type 2 diabetes: results from a meta-analysis. Hepatology 58(2):835-36
124. Chang CH, Lin JW, Wu LC, Lai MS, Chuang LM, Chan KA. 2012. Association of thiazolidinediones with liver cancer and colorectal cancer in type 2 diabetes mellitus. Hepatology 55(5):1462-72
125. Wang YM, Chai SC, Brewer CT, Chen T. 2014. Pregnane X receptor and drug-induced liver injury. Expert Opin. Drug Metab. Toxicol. 10(11):1521-32
126. Lu W, Cheng F, Jiang J, Zhang C, Deng X, et al. 2015. FXR antagonism of NSAIDs contributes to drug-induced liver injury identified by systems pharmacology approach. Sci. Rep. 5:8114
127. Zhang J, Huang W, Chua SS, Wei P, Moore DD. 2002. Modulation of acetaminophen-induced hepatotoxicity by the xenobiotic receptor CAR. Science 298(5592):422-24
128. Cheng J,Ma X, Krausz KW, Idle JR,Gonzalez FJ. 2009. Rifampicin-activated human pregnane X receptor and CYP3A4 induction enhance acetaminophen-induced toxicity. Drug Metab. Dispos 37(8):1611-21
129. Dai G, Chou N, Gyamfi MA, Mendy AJ, Slitt AL, et al. 2005. Retinoid X receptor Regulates the expression of glutathione s-transferase genes and modulates acetaminophen-glutathione conjugation in mouse liver. Mol. Pharmacol. 68(6):1590-96
130. Lee FY, de Aguiar Vallim TQ, Chong HK, Zhang Y, Liu Y, et al. 2010. Activation of the farnesoid X receptor provides protection against acetaminophen-induced hepatic toxicity. Mol. Endocrinol. 24(8):1626-36
131. Saini SP, Zhang B, Niu Y, Jiang M, Gao J, et al. 2011. Activation of liver X receptor increases acetaminophen clearance and prevents its toxicity in mice. Hepatology 54(6):2208-17
132. Bataille AM, Manautou JE. 2012. Nrf2: A potential target for new therapeutics in liver disease. Clin. Pharmacol. Ther. 92(3):340-48
133. Baskin-Bey ES, Huang W, Ishimura N, Isomoto H, Bronk SF, et al. 2006. Constitutive androstane receptor (CAR) ligand, TCPOBOP, attenuates Fas-induced murine liver injury by altering Bcl-2 proteins. Hepatology 44(1):252-62
134. Chen WD, Fu X, Dong B,Wang YD, Shiah S, et al. 2012. Neonatal activation of the nuclear receptor CAR results in epigenetic memory and permanent change of drug metabolism in mouse liver. Hepatology 56(4):1499-509
135. VenkateshM,WangH, Cayer J, Leroux M, Salvail D, et al. 2011. In vivo and in vitro characterization of a first-in-class novel azole analog that targets pregnaneXreceptor activation. Mol. Pharmacol. 80(1):124-35
136. Chen C, Hennig GE, Whiteley HE, Corton JC, Manautou JE. 2000. Peroxisome proliferator-activated receptor null mice lack resistance to acetaminophen hepatotoxicity following clofibrate exposure. Toxicol. Sci. 57(2):338-44
137. Song G, Wang L. 2009. A conserved gene structure and expression regulation of miR-433 and miR-127 in mammals. PLOS ONE 4(11):e7829
138. Song G, Wang L. 2008. MiR-433 and miR-127 arise from independent overlapping primary transcripts encoded by the miR-433-127 locus. PLOS ONE 3(10):e3574
139. Song G, Wang L. 2008. Transcriptional mechanism for the paired miR-433 and miR-127 genes by nuclear receptors SHP and ERR. Nucleic Acids Res. 36(18):5727-35
140. Yang Z, Zhang Y,Wang L. 2013. A feedback inhibition between miRNA-127 and TGF/c-Jun cascade in HCC cell migration via MMP13. PLOS ONE 8(6):e65256
141. Yang Z, Tsuchiya H, Zhang Y, Hartnett ME, Wang L. 2013. MicroRNA-433 inhibits liver cancer cell migration by repressing the protein expression and function of cAMP response element-binding protein. J. Biol. Chem. 288(40):28893-99
142. Song G, Zhang Y,Wang L. 2009. MicroRNA-206 targets notch3, activates apoptosis, and inhibits tumor cell migration and focus formation. J. Biol. Chem. 284(46):31921-27
143. Song G, Wang L. 2009. Nuclear receptor SHP activates miR-206 expression via a cascade dual inhibitory mechanism. PLOS ONE 4(9):e6880
144. Yang Z, Wang L. 2011. Regulation of microRNA expression and function by nuclear receptor signaling. Cell Biosci. 1(1):31
145. Zhang Y, Yang Z, Whitby R, Wang L. 2011. Regulation of miR-200c by nuclear receptors PPAR, LRH-1 and SHP. Biochem. Biophys. Res. Commun. 416(1-2):135-39
146. ZhiX,ZhouXE,HeY, ZechnerC, Suino-PowellKM, et al. 2014. Structural insights into gene repression by the orphan nuclear receptor SHP. PNAS 111(2):839-44