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Semin Liver Dis 2016; 36(01): 069-086
DOI: 10.1055/s-0036-1571296
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Nuclear Receptor Modulation for the Treatment of Nonalcoholic Fatty Liver Disease

Claudia D. Fuchs
1   Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
*   These authors contributed equally to this publication.
,
Stefan A. Traussnigg
1   Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
*   These authors contributed equally to this publication.
,
Michael Trauner
1   Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
› Author Affiliations
Further Information

Publication History

Publication Date:
12 February 2016 (online)

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Abstract

Nuclear receptors (NRs) are ligand-activated transcriptional regulators of several key metabolic processes including hepatic lipid and glucose metabolism, bile acid homeostasis, and energy expenditure as well as inflammation, fibrosis, and cellular proliferation in the liver. Dysregulation of these processes contributes to the pathogenesis and progression of nonalcoholic fatty liver disease (NAFLD). This places NRs at the forefront of novel therapeutic approaches for NAFLD. Some NRs are already pharmacologically targeted in metabolic disorders such as hyperlipidemia (peroxisomal proliferator-activated receptor α [PPARα], fibrates) and diabetes (PPARγ, glitazones) with potential applications for NAFLD. Other NRs with potential therapeutic implications are the vitamin D receptor (VDR) and xenobiotic sensors such as constitutive androstane receptor (CAR) and pregnane X receptor (PXR). Further new perspectives include combined ligands for NR isoforms such as PPARα/δ ligands. Other novel key players represent the nuclear bile acid receptor farnesoid X receptor (FXR; targeted by synthetic FXR ligands such as obeticholic acid) and RAR-related orphan receptor gamma two (RORγt). In this review the authors provide an overview of the preclinical and clinical evidence of current and future treatment strategies targeting NRs in metabolism, inflammation, and fibrogenesis of NAFLD.

Keywords

bile acids - farnesoid X receptor - TGR5 - FGF15/19 - fatty acids - peroxisomal proliferator-activated receptor - xenobiotic sensors - vitamin D - RAR-related orphan receptor gamma two
 

  • References

  • 1 Arrese M, Karpen SJ. Nuclear receptors, inflammation, and liver disease: insights for cholestatic and fatty liver diseases. Clin Pharmacol Ther 2010; 87 (4) 473-478
    CrossrefPubMedGoogle Scholar
  • 2 Giguère V, Yang N, Segui P, Evans RM. Identification of a new class of steroid hormone receptors. Nature 1988; 331 (6151) 91-94
    CrossrefPubMedGoogle Scholar
  • 3 Zollner G, Trauner M. Nuclear receptors as therapeutic targets in cholestatic liver diseases. Br J Pharmacol 2009; 156 (1) 7-27
    CrossrefPubMedGoogle Scholar
  • 4 Fuchs C, Claudel T, Trauner M. Bile acid-mediated control of liver triglycerides. Semin Liver Dis 2013; 33 (4) 330-342
    Article in Thieme ConnectPubMedGoogle Scholar
  • 5 Sonoda J, Pei L, Evans RM. Nuclear receptors: decoding metabolic disease. FEBS Lett 2008; 582 (1) 2-9
    CrossrefPubMedGoogle Scholar
  • 6 Wagner M, Zollner G, Trauner M. Nuclear receptors in liver disease. Hepatology 2011; 53 (3) 1023-1034
    CrossrefPubMedGoogle Scholar
  • 7 Gronemeyer H, Gustafsson JA, Laudet V. Principles for modulation of the nuclear receptor superfamily. Nat Rev Drug Discov 2004; 3 (11) 950-964
    CrossrefPubMedGoogle Scholar
  • 8 Blumberg B, Evans RM. Orphan nuclear receptors—new ligands and new possibilities. Genes Dev 1998; 12 (20) 3149-3155
    CrossrefPubMedGoogle Scholar
  • 9 Raghuram S, Stayrook KR, Huang P , et al. Identification of heme as the ligand for the orphan nuclear receptors REV-ERBalpha and REV-ERBbeta. Nat Struct Mol Biol 2007; 14 (12) 1207-1213
    CrossrefPubMedGoogle Scholar
  • 10 Santori FR, Huang P, van de Pavert SA , et al. Identification of natural RORγ ligands that regulate the development of lymphoid cells. Cell Metab 2015; 21 (2) 286-297
    CrossrefPubMedGoogle Scholar
  • 11 Angulo P. Nonalcoholic fatty liver disease. N Engl J Med 2002; 346 (16) 1221-1231
    CrossrefPubMedGoogle Scholar
  • 12 Keller H, Dreyer C, Medin J, Mahfoudi A, Ozato K, Wahli W. Fatty acids and retinoids control lipid metabolism through activation of peroxisome proliferator-activated receptor-retinoid X receptor heterodimers. Proc Natl Acad Sci U S A 1993; 90 (6) 2160-2164
    CrossrefPubMedGoogle Scholar
  • 13 Willson TM, Brown PJ, Sternbach DD, Henke BR. The PPARs: from orphan receptors to drug discovery. J Med Chem 2000; 43 (4) 527-550
    CrossrefPubMedGoogle Scholar
  • 14 Repa JJ, Liang G, Ou J , et al. Regulation of mouse sterol regulatory element-binding protein-1c gene (SREBP-1c) by oxysterol receptors, LXRalpha and LXRbeta. Genes Dev 2000; 14 (22) 2819-2830
    CrossrefPubMedGoogle Scholar
  • 15 Peet DJ, Turley SD, Ma W , et al. Cholesterol and bile acid metabolism are impaired in mice lacking the nuclear oxysterol receptor LXR alpha. Cell 1998; 93 (5) 693-704
    CrossrefPubMedGoogle Scholar
  • 16 Makishima M, Okamoto AY, Repa JJ , et al. Identification of a nuclear receptor for bile acids. Science 1999; 284 (5418) 1362-1365
    CrossrefPubMedGoogle Scholar
  • 17 Parks DJ, Blanchard SG, Bledsoe RK , et al. Bile acids: natural ligands for an orphan nuclear receptor. Science 1999; 284 (5418) 1365-1368
    CrossrefPubMedGoogle Scholar
  • 18 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 (5) 543-553
    PubMedGoogle Scholar
  • 19 Mudaliar S, Henry RR, Sanyal AJ , et al. Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease. Gastroenterology 2013; 145 (3) 574-82.e1
    CrossrefPubMedGoogle Scholar
  • 20 Paschos P, Paletas K. Non alcoholic fatty liver disease and metabolic syndrome. Hippokratia 2009; 13 (1) 9-19
    PubMedGoogle Scholar
  • 21 Tailleux A, Wouters K, Staels B. Roles of PPARs in NAFLD: potential therapeutic targets. Biochim Biophys Acta 2012; 1821 (5) 809-818
    CrossrefPubMedGoogle Scholar
  • 22 Lefebvre P, Chinetti G, Fruchart JC, Staels B. Sorting out the roles of PPAR alpha in energy metabolism and vascular homeostasis. J Clin Invest 2006; 116 (3) 571-580
    CrossrefPubMedGoogle Scholar
  • 23 Staels B, Maes M, Zambon A. Fibrates and future PPARalpha agonists in the treatment of cardiovascular disease. Nat Clin Pract Cardiovasc Med 2008; 5 (9) 542-553
    CrossrefPubMedGoogle Scholar
  • 24 Minnich A, Tian N, Byan L, Bilder G. A potent PPARalpha agonist stimulates mitochondrial fatty acid beta-oxidation in liver and skeletal muscle. Am J Physiol Endocrinol Metab 2001; 280 (2) E270-E279
    PubMedGoogle Scholar
  • 25 Staels B, Vu-Dac N, Kosykh VA , et al. Fibrates downregulate apolipoprotein C-III expression independent of induction of peroxisomal acyl coenzyme A oxidase. A potential mechanism for the hypolipidemic action of fibrates. J Clin Invest 1995; 95 (2) 705-712
    CrossrefPubMedGoogle Scholar
  • 26 Kleemann R, Gervois PP, Verschuren L, Staels B, Princen HM, Kooistra T. Fibrates down-regulate IL-1-stimulated C-reactive protein gene expression in hepatocytes by reducing nuclear p50-NFkappa B-C/EBP-beta complex formation. Blood 2003; 101 (2) 545-551
    CrossrefPubMedGoogle Scholar
  • 27 Staels B, Koenig W, Habib A , et al. Activation of human aortic smooth-muscle cells is inhibited by PPARalpha but not by PPARgamma activators. Nature 1998; 393 (6687) 790-793
    CrossrefPubMedGoogle Scholar
  • 28 Belvisi MG, Mitchell JA. Targeting PPAR receptors in the airway for the treatment of inflammatory lung disease. Br J Pharmacol 2009; 158 (4) 994-1003
    CrossrefPubMedGoogle Scholar
  • 29 Hashimoto T, Cook WS, Qi C, Yeldandi AV, Reddy JK, Rao MS. Defect in peroxisome proliferator-activated receptor alpha-inducible fatty acid oxidation determines the severity of hepatic steatosis in response to fasting. J Biol Chem 2000; 275 (37) 28918-28928
    CrossrefPubMedGoogle Scholar
  • 30 Hashimoto T, Fujita T, Usuda N , et al. Peroxisomal and mitochondrial fatty acid beta-oxidation in mice nullizygous for both peroxisome proliferator-activated receptor alpha and peroxisomal fatty acyl-CoA oxidase. Genotype correlation with fatty liver phenotype. J Biol Chem 1999; 274 (27) 19228-19236
    CrossrefPubMedGoogle Scholar
  • 31 Gavrilova O, Haluzik M, Matsusue K , et al. Liver peroxisome proliferator-activated receptor gamma contributes to hepatic steatosis, triglyceride clearance, and regulation of body fat mass. J Biol Chem 2003; 278 (36) 34268-34276
    CrossrefPubMedGoogle Scholar
  • 32 Matsusue K, Haluzik M, Lambert G , et al. Liver-specific disruption of PPARgamma in leptin-deficient mice improves fatty liver but aggravates diabetic phenotypes. J Clin Invest 2003; 111 (5) 737-747
    CrossrefPubMedGoogle Scholar
  • 33 Lalloyer F, Staels B. Fibrates, glitazones, and peroxisome proliferator-activated receptors. Arterioscler Thromb Vasc Biol 2010; 30 (5) 894-899
    CrossrefPubMedGoogle Scholar
  • 34 Fiévet C, Staels B. Efficacy of peroxisome proliferator-activated receptor agonists in diabetes and coronary artery disease. Curr Atheroscler Rep 2009; 11 (4) 281-288
    CrossrefPubMedGoogle Scholar
  • 35 Qin X, Xie X, Fan Y , et al. Peroxisome proliferator-activated receptor-delta induces insulin-induced gene-1 and suppresses hepatic lipogenesis in obese diabetic mice. Hepatology 2008; 48 (2) 432-441
    CrossrefPubMedGoogle Scholar
  • 36 Ip E, Farrell GC, Robertson G, Hall P, Kirsch R, Leclercq I. Central role of PPARalpha-dependent hepatic lipid turnover in dietary steatohepatitis in mice. Hepatology 2003; 38 (1) 123-132
    CrossrefPubMedGoogle Scholar
  • 37 Stienstra R, Mandard S, Patsouris D, Maass C, Kersten S, Müller M. Peroxisome proliferator-activated receptor alpha protects against obesity-induced hepatic inflammation. Endocrinology 2007; 148 (6) 2753-2763
    CrossrefPubMedGoogle Scholar
  • 38 Lalloyer F, Wouters K, Baron M , et al. Peroxisome proliferator-activated receptor-alpha gene level differently affects lipid metabolism and inflammation in apolipoprotein E2 knock-in mice. Arterioscler Thromb Vasc Biol 2011; 31 (7) 1573-1579
    CrossrefPubMedGoogle Scholar
  • 39 Shiri-Sverdlov R, Wouters K, van Gorp PJ , et al. Early diet-induced non-alcoholic steatohepatitis in APOE2 knock-in mice and its prevention by fibrates. J Hepatol 2006; 44 (4) 732-741
    CrossrefPubMedGoogle Scholar
  • 40 Ip E, Farrell G, Hall P, Robertson G, Leclercq I. Administration of the potent PPARalpha agonist, Wy-14,643, reverses nutritional fibrosis and steatohepatitis in mice. Hepatology 2004; 39 (5) 1286-1296
    CrossrefPubMedGoogle Scholar
  • 41 Kleemann R, Verschuren L, de Rooij BJ , et al. Evidence for anti-inflammatory activity of statins and PPARalpha activators in human C-reactive protein transgenic mice in vivo and in cultured human hepatocytes in vitro. Blood 2004; 103 (11) 4188-4194
    CrossrefPubMedGoogle Scholar
  • 42 Bensinger SJ, Tontonoz P. Integration of metabolism and inflammation by lipid-activated nuclear receptors. Nature 2008; 454 (7203) 470-477
    CrossrefPubMedGoogle Scholar
  • 43 Francque S, Verrijken A, Caron S , et al. PPARα gene expression correlates with severity and histological treatment response in patients with non-alcoholic steatohepatitis. J Hepatol 2015; 63 (1) 164-173
    CrossrefPubMedGoogle Scholar
  • 44 Souza-Mello V. Peroxisome proliferator-activated receptors as targets to treat non-alcoholic fatty liver disease. World J Hepatol 2015; 7 (8) 1012-1019
    CrossrefPubMedGoogle Scholar
  • 45 Chapman MJ. Fibrates in 2003: therapeutic action in atherogenic dyslipidaemia and future perspectives. Atherosclerosis 2003; 171 (1) 1-13
    CrossrefPubMedGoogle Scholar
  • 46 Berglund L, Brunzell JD, Goldberg AC , et al; Endocrine society. Evaluation and treatment of hypertriglyceridemia: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2012; 97 (9) 2969-2989
    CrossrefPubMedGoogle Scholar
  • 47 Keech A, Simes RJ, Barter P , et al; FIELD study investigators. 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
    CrossrefPubMedGoogle Scholar
  • 48 Ong JP, Pitts A, Younossi ZM. Increased overall mortality and liver-related mortality in non-alcoholic fatty liver disease. J Hepatol 2008; 49 (4) 608-612
    CrossrefPubMedGoogle Scholar
  • 49 Ekstedt M, Hagström H, Nasr P , et al. Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up. Hepatology 2015; 61 (5) 1547-1554
    CrossrefPubMedGoogle Scholar
  • 50 Kostapanos MS, Kei A, Elisaf MS. Current role of fenofibrate in the prevention and management of non-alcoholic fatty liver disease. World J Hepatol 2013; 5 (9) 470-478
    CrossrefPubMedGoogle Scholar
  • 51 Athyros VG, Mikhailidis DP, Didangelos TP , et al. Effect of multifactorial treatment on non-alcoholic fatty liver disease in metabolic syndrome: a randomised study. Curr Med Res Opin 2006; 22 (5) 873-883
    CrossrefPubMedGoogle Scholar
  • 52 Bajaj M, Suraamornkul S, Hardies LJ, Glass L, Musi N, DeFronzo RA. Effects of peroxisome proliferator-activated receptor (PPAR)-alpha and PPAR-gamma agonists on glucose and lipid metabolism in patients with type 2 diabetes mellitus. Diabetologia 2007; 50 (8) 1723-1731
    CrossrefPubMedGoogle Scholar
  • 53 Fernández-Miranda C, Pérez-Carreras M, Colina F, López-Alonso G, Vargas C, Solís-Herruzo JA. A pilot trial of fenofibrate for the treatment of non-alcoholic fatty liver disease. Dig Liver Dis 2008; 40 (3) 200-205
    CrossrefPubMedGoogle Scholar
  • 54 Laurin J, Lindor KD, Crippin JS , et al. Ursodeoxycholic acid or clofibrate in the treatment of non-alcohol-induced steatohepatitis: a pilot study. Hepatology 1996; 23 (6) 1464-1467
    CrossrefPubMedGoogle Scholar
  • 55 Parker HM, Johnson NA, Burdon CA, Cohn JS, O'Connor HT, George J. Omega-3 supplementation and non-alcoholic fatty liver disease: a systematic review and meta-analysis. J Hepatol 2012; 56 (4) 944-951
    CrossrefPubMedGoogle Scholar
  • 56 Shapiro H, Tehilla M, Attal-Singer J, Bruck R, Luzzatti R, Singer P. The therapeutic potential of long-chain omega-3 fatty acids in nonalcoholic fatty liver disease. Clin Nutr 2011; 30 (1) 6-19
    CrossrefPubMedGoogle Scholar
  • 57 Nogueira MA, Oliveira CP, Ferreira Alves VA , et al. Omega-3 polyunsaturated fatty acids in treating non-alcoholic steatohepatitis: A randomized, double-blind, placebo-controlled trial. Clin Nutr 2015;
    PubMedGoogle Scholar
  • 58 Fruchart JC. Selective peroxisome proliferator-activated receptor α modulators (SPPARMα): the next generation of peroxisome proliferator-activated receptor α-agonists. Cardiovasc Diabetol 2013; 12: 82
    CrossrefPubMedGoogle Scholar
  • 59 Cariou B, Hanf R, Lambert-Porcheron S , et al. Dual peroxisome proliferator-activated receptor α/δ agonist GFT505 improves hepatic and peripheral insulin sensitivity in abdominally obese subjects. Diabetes Care 2013; 36 (10) 2923-2930
    CrossrefPubMedGoogle Scholar
  • 60 Staels B, Rubenstrunk A, Noel B , et al. Hepatoprotective effects of the dual peroxisome proliferator-activated receptor alpha/delta agonist, GFT505, in rodent models of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. Hepatology 2013; 58 (6) 1941-1952
    CrossrefPubMedGoogle Scholar
  • 61 Ratziu V, Bedossa P , et al. An international, phase 2 randomized controlled trial of the dual PPAR α-δ agonist GFT505 in adult patients with NASH. Hepatology 2015; 62 (S1): 262A
    CrossrefPubMedGoogle Scholar
  • 62 Nan YM, Han F, Kong LB , et al. Adenovirus-mediated peroxisome proliferator activated receptor gamma overexpression prevents nutritional fibrotic steatohepatitis in mice. Scand J Gastroenterol 2011; 46 (3) 358-369
    CrossrefPubMedGoogle Scholar
  • 63 Frayn KN. Adipose tissue as a buffer for daily lipid flux. Diabetologia 2002; 45 (9) 1201-1210
    CrossrefPubMedGoogle Scholar
  • 64 Maeda N, Takahashi M, Funahashi T , et al. PPARgamma ligands increase expression and plasma concentrations of adiponectin, an adipose-derived protein. Diabetes 2001; 50 (9) 2094-2099
    CrossrefPubMedGoogle Scholar
  • 65 Yamauchi T, Kamon J, Waki H , et al. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med 2001; 7 (8) 941-946
    CrossrefPubMedGoogle Scholar
  • 66 Yamauchi T, Kamon J, Ito Y , et al. Cloning of adiponectin receptors that mediate antidiabetic metabolic effects. Nature 2003; 423 (6941) 762-769
    CrossrefPubMedGoogle Scholar
  • 67 Galli A, Crabb D, Price D , et al. Peroxisome proliferator-activated receptor gamma transcriptional regulation is involved in platelet-derived growth factor-induced proliferation of human hepatic stellate cells. Hepatology 2000; 31 (1) 101-108
    CrossrefPubMedGoogle Scholar
  • 68 Miyahara T, Schrum L, Rippe R , et al. Peroxisome proliferator-activated receptors and hepatic stellate cell activation. J Biol Chem 2000; 275 (46) 35715-35722
    CrossrefPubMedGoogle Scholar
  • 69 Marra F, Efsen E, Romanelli RG , et al. Ligands of peroxisome proliferator-activated receptor gamma modulate profibrogenic and proinflammatory actions in hepatic stellate cells. Gastroenterology 2000; 119 (2) 466-478
    CrossrefPubMedGoogle Scholar
  • 70 Zhao C, Chen W, Yang L, Chen L, Stimpson SA, Diehl AM. PPARgamma agonists prevent TGFbeta1/Smad3-signaling in human hepatic stellate cells. Biochem Biophys Res Commun 2006; 350 (2) 385-391
    CrossrefPubMedGoogle Scholar
  • 71 She H, Xiong S, Hazra S, Tsukamoto H. Adipogenic transcriptional regulation of hepatic stellate cells. J Biol Chem 2005; 280 (6) 4959-4967
    CrossrefPubMedGoogle Scholar
  • 72 Wang X, Huang G, Mei S, Qian J, Ji J, Zhang J. Over-expression of C/EBP-alpha induces apoptosis in cultured rat hepatic stellate cells depending on p53 and peroxisome proliferator-activated receptor-gamma. Biochem Biophys Res Commun 2009; 380 (2) 286-291
    CrossrefPubMedGoogle Scholar
  • 73 Chinetti G, Fruchart JC, Staels B. Peroxisome proliferator-activated receptors: new targets for the pharmacological modulation of macrophage gene expression and function. Curr Opin Lipidol 2003; 14 (5) 459-468
    CrossrefPubMedGoogle Scholar
  • 74 Bouhlel MA, Derudas B, Rigamonti E , et al. PPARgamma activation primes human monocytes into alternative M2 macrophages with anti-inflammatory properties. Cell Metab 2007; 6 (2) 137-143
    CrossrefPubMedGoogle Scholar
  • 75 Foryst-Ludwig A, Hartge M, Clemenz M , et al. PPARgamma activation attenuates T-lymphocyte-dependent inflammation of adipose tissue and development of insulin resistance in obese mice. Cardiovasc Diabetol 2010; 9: 64
    CrossrefPubMedGoogle Scholar
  • 76 Watanabe S, Hashimoto E, Ikejima K , et al. Evidence-based clinical practice guidelines for nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. J Gastroenterol 2015; 50 (4) 364-377
    CrossrefPubMedGoogle Scholar
  • 77 Chalasani N, Younossi Z, Lavine JE , et al. The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology 2012; 55 (6) 2005-2023
    CrossrefPubMedGoogle Scholar
  • 78 Belfort R, Harrison SA, Brown K , et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med 2006; 355 (22) 2297-2307
    CrossrefPubMedGoogle Scholar
  • 79 Ratziu V, Giral P, Jacqueminet S , et al; LIDO Study Group. Rosiglitazone for nonalcoholic steatohepatitis: one-year results of the randomized placebo-controlled Fatty Liver Improvement with Rosiglitazone Therapy (FLIRT) Trial. Gastroenterology 2008; 135 (1) 100-110
    CrossrefPubMedGoogle Scholar
  • 80 Smith SR, De Jonge L, Volaufova J, Li Y, Xie H, Bray GA. Effect of pioglitazone on body composition and energy expenditure: a randomized controlled trial. Metabolism 2005; 54 (1) 24-32
    PubMedGoogle Scholar
  • 81 Ratziu V, Charlotte F, Bernhardt C , et al; LIDO Study Group. Long-term efficacy of rosiglitazone in nonalcoholic steatohepatitis: results of the fatty liver improvement by rosiglitazone therapy (FLIRT 2) extension trial. Hepatology 2010; 51 (2) 445-453
    CrossrefPubMedGoogle Scholar
  • 82 Sanyal AJ, Chalasani N, Kowdley KV , et al; NASH CRN. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med 2010; 362 (18) 1675-1685
    CrossrefPubMedGoogle Scholar
  • 83 Sanyal AJ, Mofrad PS, Contos MJ , et al. A pilot study of vitamin E versus vitamin E and pioglitazone for the treatment of nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol 2004; 2 (12) 1107-1115
    CrossrefPubMedGoogle Scholar
  • 84 Neuschwander-Tetri BA, Brunt EM, Wehmeier KR, Oliver D, Bacon BR. Improved nonalcoholic steatohepatitis after 48 weeks of treatment with the PPAR-gamma ligand rosiglitazone. Hepatology 2003; 38 (4) 1008-1017
    CrossrefPubMedGoogle Scholar
  • 85 Caldwell SH, Hespenheide EE, Redick JA, Iezzoni JC, Battle EH, Sheppard BL. A pilot study of a thiazolidinedione, troglitazone, in nonalcoholic steatohepatitis. Am J Gastroenterol 2001; 96 (2) 519-525
    CrossrefPubMedGoogle Scholar
  • 86 Ratziu V, Caldwell S, Neuschwander-Tetri BA. Therapeutic trials in nonalcoholic steatohepatitis: insulin sensitizers and related methodological issues. Hepatology 2010; 52 (6) 2206-2215
    CrossrefPubMedGoogle Scholar
  • 87 Cusi K, Orsak B, Lomonaco R , et al. Extended treatment with pioglitazone improves liver histology in patients with prediabetes or type 2 diabetes mellitus and NASH. Hepatology 2013; 58 (S1): 248A
    PubMedGoogle Scholar
  • 88 Nissen SE, 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
    CrossrefPubMedGoogle Scholar
  • 89 Mahaffey KW, Hafley G, Dickerson S , et al. Results of a reevaluation of cardiovascular outcomes in the RECORD trial. Am Heart J 2013; 166 (2) 240-249.e1
    CrossrefPubMedGoogle Scholar
  • 90 Dormandy JA, Charbonnel B, Eckland DJ , et al; PROactive investigators. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet 2005; 366 (9493) 1279-1289
    CrossrefPubMedGoogle Scholar
  • 91 Erdmann E, Song E, Spanheimer R, van Troostenburg de Bruyn AR, Perez A. Observational follow-up of the PROactive study: a 6-year update. Diabetes Obes Metab 2014; 16 (1) 63-74
    CrossrefPubMedGoogle Scholar
  • 92 Turner RM, Kwok CS, Chen-Turner C, Maduakor CA, Singh S, Loke YK. Thiazolidinediones and associated risk of bladder cancer: a systematic review and meta-analysis. Br J Clin Pharmacol 2014; 78 (2) 258-273
    CrossrefPubMedGoogle Scholar
  • 93 Levin D, Bell S, Sund R , et al; Scottish Diabetes Research Network Epidemiology Group; Diabetes and Cancer Research Consortium. Pioglitazone and bladder cancer risk: a multipopulation pooled, cumulative exposure analysis. Diabetologia 2015; 58 (3) 493-504
    CrossrefPubMedGoogle Scholar
  • 94 Xie X, Zhou X, Chen W , et al. L312, a novel PPARγ ligand with potent anti-diabetic activity by selective regulation. Biochim Biophys Acta 2015; 1850 (1) 62-72
    CrossrefPubMedGoogle Scholar
  • 95 DePaoli AM, Higgins LS, Henry RR, Mantzoros C, Dunn FL ; INT131-007 Study Group. Can a selective PPARγ modulator improve glycemic control in patients with type 2 diabetes with fewer side effects compared with pioglitazone?. Diabetes Care 2014; 37 (7) 1918-1923
    CrossrefPubMedGoogle Scholar
  • 96 Singh S, Singh PP, Singh AG, Murad MH, Sanchez W. Anti-diabetic medications and the risk of hepatocellular cancer: a systematic review and meta-analysis. Am J Gastroenterol 2013; 108 (6) 881-891 , quiz 892
    CrossrefPubMedGoogle Scholar
  • 97 Chen H-P, Shieh JJ, Chang CC , et al. Metformin decreases hepatocellular carcinoma risk in a dose-dependent manner: population-based and in vitro studies. Gut 2013; 62 (4) 606-615
    CrossrefPubMedGoogle Scholar
  • 98 Nagasawa T, Inada Y, Nakano S , et al. Effects of bezafibrate, PPAR pan-agonist, and GW501516, PPARdelta agonist, on development of steatohepatitis in mice fed a methionine- and choline-deficient diet. Eur J Pharmacol 2006; 536 (1–2) 182-191
    CrossrefPubMedGoogle Scholar
  • 99 Hoekstra M, Kruijt JK, Van Eck M, Van Berkel TJ. Specific gene expression of ATP-binding cassette transporters and nuclear hormone receptors in rat liver parenchymal, endothelial, and Kupffer cells. J Biol Chem 2003; 278 (28) 25448-25453
    CrossrefPubMedGoogle Scholar
  • 100 Kang K, Reilly SM, Karabacak V , et al. Adipocyte-derived Th2 cytokines and myeloid PPARdelta regulate macrophage polarization and insulin sensitivity. Cell Metab 2008; 7 (6) 485-495
    CrossrefPubMedGoogle Scholar
  • 101 Odegaard JI, Ricardo-Gonzalez RR, Red Eagle A , et al. Alternative M2 activation of Kupffer cells by PPARdelta ameliorates obesity-induced insulin resistance. Cell Metab 2008; 7 (6) 496-507
    CrossrefPubMedGoogle Scholar
  • 102 Sprecher DL, Massien C, Pearce G , et al. Triglyceride:high-density lipoprotein cholesterol effects in healthy subjects administered a peroxisome proliferator activated receptor delta agonist. Arterioscler Thromb Vasc Biol 2007; 27 (2) 359-365
    PubMedGoogle Scholar
  • 103 Risérus U, Sprecher D, Johnson T , et al. 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
    CrossrefPubMedGoogle Scholar
  • 104 Olson EJ, Pearce GL, Jones NP, Sprecher DL. Lipid effects of peroxisome proliferator-activated receptor-δ agonist GW501516 in subjects with low high-density lipoprotein cholesterol: characteristics of metabolic syndrome. Arterioscler Thromb Vasc Biol 2012; 32 (9) 2289-2294
    CrossrefPubMedGoogle Scholar
  • 105 Bays HE, Schwartz S, Littlejohn III T , et al. MBX-8025, a novel peroxisome proliferator receptor-delta agonist: lipid and other metabolic effects in dyslipidemic overweight patients treated with and without atorvastatin. J Clin Endocrinol Metab 2011; 96 (9) 2889-2897
    CrossrefPubMedGoogle Scholar
  • 106 Ehrenborg E, Skogsberg J. Peroxisome proliferator-activated receptor delta and cardiovascular disease. Atherosclerosis 2013; 231 (1) 95-106
    CrossrefPubMedGoogle Scholar
  • 107 Sahebkar A, Chew GT, Watts GF. New peroxisome proliferator-activated receptor agonists: potential treatments for atherogenic dyslipidemia and non-alcoholic fatty liver disease. Expert Opin Pharmacother 2014; 15 (4) 493-503
    CrossrefPubMedGoogle Scholar
  • 108 Iwaisako K, Haimerl M, Paik YH , et al. Protection from liver fibrosis by a peroxisome proliferator-activated receptor δ agonist. Proc Natl Acad Sci U S A 2012; 109 (21) E1369-E1376
    CrossrefPubMedGoogle Scholar
  • 109 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 (1) 147-191
    CrossrefPubMedGoogle Scholar
  • 110 Adorini L, Pruzanski M, Shapiro D. Farnesoid X receptor targeting to treat nonalcoholic steatohepatitis. Drug Discov Today 2012; 17 (17–18) 988-997
    CrossrefPubMedGoogle Scholar
  • 111 Thomas C, Pellicciari R, Pruzanski M, Auwerx J, Schoonjans K. Targeting bile-acid signalling for metabolic diseases. Nat Rev Drug Discov 2008; 7 (8) 678-693
    CrossrefPubMedGoogle Scholar
  • 112 Tsuei J, Chau T, Mills D, Wan YJ. Bile acid dysregulation, gut dysbiosis, and gastrointestinal cancer. Exp Biol Med (Maywood) 2014; 239 (11) 1489-1504
    CrossrefPubMedGoogle Scholar
  • 113 Ghiassi-Nejad Z, Friedman SL. Advances in antifibrotic therapy. Expert Rev Gastroenterol Hepatol 2008; 2 (6) 803-816
    CrossrefPubMedGoogle Scholar
  • 114 Zhang Y, Edwards PA. FXR signaling in metabolic disease. FEBS Lett 2008; 582 (1) 10-18
    CrossrefPubMedGoogle Scholar
  • 115 Staels B, Handelsman Y, Fonseca V. Bile acid sequestrants for lipid and glucose control. Curr Diab Rep 2010; 10 (1) 70-77
    CrossrefPubMedGoogle Scholar
  • 116 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
    CrossrefPubMedGoogle Scholar
  • 117 Chiang JY. Bile acids: regulation of synthesis. J Lipid Res 2009; 50 (10) 1955-1966
    CrossrefPubMedGoogle Scholar
  • 118 Kir S, Zhang Y, Gerard RD, Kliewer SA, Mangelsdorf DJ. Nuclear receptors HNF4α and LRH-1 cooperate in regulating Cyp7a1 in vivo. J Biol Chem 2012; 287 (49) 41334-41341
    CrossrefPubMedGoogle Scholar
  • 119 Cicione C, Degirolamo C, Moschetta A. Emerging role of fibroblast growth factors 15/19 and 21 as metabolic integrators in the liver. Hepatology 2012; 56 (6) 2404-2411
    CrossrefPubMedGoogle Scholar
  • 120 Trabelsi MS, Daoudi M, Prawitt J , et al. Farnesoid X receptor inhibits glucagon-like peptide-1 production by enteroendocrine L cells. Nat Commun 2015; 6: 7629
    CrossrefPubMedGoogle Scholar
  • 121 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
    CrossrefPubMedGoogle Scholar
  • 122 Watanabe M, Houten SM, Mataki C , et al. Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature 2006; 439 (7075) 484-489
    CrossrefPubMedGoogle Scholar
  • 123 Prawitt J, Caron S, Staels B. Bile acid metabolism and the pathogenesis of type 2 diabetes. Curr Diab Rep 2011; 11 (3) 160-166
    CrossrefPubMedGoogle Scholar
  • 124 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 (6) 731-744
    CrossrefPubMedGoogle Scholar
  • 125 Yang F, Huang X, Yi T, Yen Y, Moore DD, Huang W. Spontaneous development of liver tumors in the absence of the bile acid receptor farnesoid X receptor. Cancer Res 2007; 67 (3) 863-867
    CrossrefPubMedGoogle Scholar
  • 126 Guo F, Xu Z, Zhang Y , et al. FXR induces SOCS3 and suppresses hepatocellular carcinoma. Oncotarget 2015; 6 (33) 34606-34616
    PubMedGoogle Scholar
  • 127 Liu X, Zhang X, Ji L, Gu J, Zhou M, Chen S. Farnesoid X receptor associates with β-catenin and inhibits its activity in hepatocellular carcinoma. Oncotarget 2015; 6 (6) 4226-4238
    CrossrefPubMedGoogle Scholar
  • 128 Degirolamo C, Modica S, Vacca M , et al. Prevention of spontaneous hepatocarcinogenesis in farnesoid X receptor-null mice by intestinal-specific farnesoid X receptor reactivation. Hepatology 2015; 61 (1) 161-170
    CrossrefPubMedGoogle Scholar
  • 129 Uriarte I, Latasa MU, Carotti S , et al. Ileal FGF15 contributes to fibrosis-associated hepatocellular carcinoma development. Int J Cancer 2015; 136 (10) 2469-2475
    CrossrefPubMedGoogle Scholar
  • 130 Gauglhofer C, Paur J, Schrottmaier WC , et al. Fibroblast growth factor receptor 4: a putative key driver for the aggressive phenotype of hepatocellular carcinoma. Carcinogenesis 2014; 35 (10) 2331-2338
    CrossrefPubMedGoogle Scholar
  • 131 Chen Z, Xie B, Zhu Q , et al. FGFR4 and TGF-β1 expression in hepatocellular carcinoma: correlation with clinicopathological features and prognosis. Int J Med Sci 2013; 10 (13) 1868-1875
    CrossrefPubMedGoogle Scholar
  • 132 Watanabe M, Houten SM, Wang L , et al. Bile acids lower triglyceride levels via a pathway involving FXR, SHP, and SREBP-1c. J Clin Invest 2004; 113 (10) 1408-1418
    CrossrefPubMedGoogle Scholar
  • 133 Savkur RS, Bramlett KS, Michael LF, Burris TP. Regulation of pyruvate dehydrogenase kinase expression by the farnesoid X receptor. Biochem Biophys Res Commun 2005; 329 (1) 391-396
    CrossrefPubMedGoogle Scholar
  • 134 Zhang S, Wang J, Liu Q, Harnish DC. Farnesoid X receptor agonist WAY-362450 attenuates liver inflammation and fibrosis in murine model of non-alcoholic steatohepatitis. J Hepatol 2009; 51 (2) 380-388
    CrossrefPubMedGoogle Scholar
  • 135 Pellicciari R, Fiorucci S, Camaioni E , et al. 6alpha-ethyl-chenodeoxycholic acid (6-ECDCA), a potent and selective FXR agonist endowed with anticholestatic activity. J Med Chem 2002; 45 (17) 3569-3572
    CrossrefPubMedGoogle Scholar
  • 136 Baghdasaryan A, Claudel T, Gumhold J , et al. Dual farnesoid X receptor/TGR5 agonist INT-767 reduces liver injury in the Mdr2-/- (Abcb4-/-) mouse cholangiopathy model by promoting biliary HCO- 3 output. Hepatology 2011; 54 (4) 1303-1312
    CrossrefPubMedGoogle Scholar
  • 137 Vignozzi L, Morelli A, Filippi S , et al. Farnesoid X receptor activation improves erectile function in animal models of metabolic syndrome and diabetes. J Sex Med 2011; 8 (1) 57-77
    CrossrefPubMedGoogle Scholar
  • 138 Wang XX, Jiang T, Shen Y , et al. The farnesoid X receptor modulates renal lipid metabolism and diet-induced renal inflammation, fibrosis, and proteinuria. Am J Physiol Renal Physiol 2009; 297 (6) F1587-F1596
    CrossrefPubMedGoogle Scholar
  • 139 Wang XX, Jiang T, Shen Y , et al. 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
    CrossrefPubMedGoogle Scholar
  • 140 Neuschwander-Tetri BA, Loomba R, Sanyal AJ , et al; 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 (9972) 956-965
    CrossrefPubMedGoogle Scholar
  • 141 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
    CrossrefPubMedGoogle Scholar
  • 142 Sipka S, Bruckner G. The immunomodulatory role of bile acids. Int Arch Allergy Immunol 2014; 165 (1) 1-8
    CrossrefPubMedGoogle Scholar
  • 143 Wagner M, Zollner G, Trauner M. Nuclear bile acid receptor farnesoid X receptor meets nuclear factor-kappaB: new insights into hepatic inflammation. Hepatology 2008; 48 (5) 1383-1386
    CrossrefPubMedGoogle Scholar
  • 144 Vavassori P, Mencarelli A, Renga B, Distrutti E, Fiorucci S. The bile acid receptor FXR is a modulator of intestinal innate immunity. J Immunol 2009; 183 (10) 6251-6261
    CrossrefPubMedGoogle Scholar
  • 145 Gadaleta RM, van Erpecum KJ, Oldenburg B , et al. Farnesoid X receptor activation inhibits inflammation and preserves the intestinal barrier in inflammatory bowel disease. Gut 2011; 60 (4) 463-472
    CrossrefPubMedGoogle Scholar
  • 146 Mencarelli A, Renga B, Distrutti E, Fiorucci S. Antiatherosclerotic effect of farnesoid X receptor. Am J Physiol Heart Circ Physiol 2009; 296 (2) H272-H281
    PubMedGoogle Scholar
  • 147 Hartman HB, Gardell SJ, Petucci CJ, Wang S, Krueger JA, Evans MJ. Activation of farnesoid X receptor prevents atherosclerotic lesion formation in LDLR-/- and apoE-/- mice. J Lipid Res 2009; 50 (6) 1090-1100
    CrossrefPubMedGoogle Scholar
  • 148 Hambruch E, Miyazaki-Anzai S, Hahn U , et al. Synthetic farnesoid X receptor agonists induce high-density lipoprotein-mediated transhepatic cholesterol efflux in mice and monkeys and prevent atherosclerosis in cholesteryl ester transfer protein transgenic low-density lipoprotein receptor (-/-) mice. J Pharmacol Exp Ther 2012; 343 (3) 556-567
    CrossrefPubMedGoogle Scholar
  • 149 Li YT, Swales KE, Thomas GJ, Warner TD, Bishop-Bailey D. Farnesoid x receptor ligands inhibit vascular smooth muscle cell inflammation and migration. Arterioscler Thromb Vasc Biol 2007; 27 (12) 2606-2611
    CrossrefPubMedGoogle Scholar
  • 150 Trauner M, Graziadei IW. Review article: mechanisms of action and therapeutic applications of ursodeoxycholic acid in chronic liver diseases. Aliment Pharmacol Ther 1999; 13 (8) 979-996
    CrossrefPubMedGoogle Scholar
  • 151 Tsuchida T, Shiraishi M, Ohta T, Sakai K, Ishii S. Ursodeoxycholic acid improves insulin sensitivity and hepatic steatosis by inducing the excretion of hepatic lipids in high-fat diet-fed KK-Ay mice. Metabolism 2012; 61 (7) 944-953
    CrossrefPubMedGoogle Scholar
  • 152 Ozcan U, Yilmaz E, Ozcan L , et al. Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes. Science 2006; 313 (5790) 1137-1140
    CrossrefPubMedGoogle Scholar
  • 153 Legry V, Van Rooyen DM, Lambert B , et al. Endoplasmic reticulum stress does not contribute to steatohepatitis in obese and insulin-resistant high-fat-diet-fed foz/foz mice. Clin Sci (Lond) 2014; 127 (7) 507-518
    CrossrefPubMedGoogle Scholar
  • 154 Moustafa T, Fickert P, Magnes C , et al. Alterations in lipid metabolism mediate inflammation, fibrosis, and proliferation in a mouse model of chronic cholestatic liver injury. Gastroenterology 2012; 142 (1) 140-151.e12
    CrossrefPubMedGoogle Scholar
  • 155 Trauner M, Claudel T, Fickert P, Moustafa T, Wagner M. Bile acids as regulators of hepatic lipid and glucose metabolism. Dig Dis 2010; 28 (1) 220-224
    CrossrefPubMedGoogle Scholar
  • 156 Beraza N, Ofner-Ziegenfuss L, Ehedego H , et al. Nor-ursodeoxycholic acid reverses hepatocyte-specific nemo-dependent steatohepatitis. Gut 2011; 60 (3) 387-396
    CrossrefPubMedGoogle Scholar
  • 157 Jiang C, Xie C, Li F , et al. Intestinal farnesoid X receptor signaling promotes nonalcoholic fatty liver disease. J Clin Invest 2015; 125 (1) 386-402
    CrossrefPubMedGoogle Scholar
  • 158 Li F, Jiang C, Krausz KW , et al. Microbiome remodelling leads to inhibition of intestinal farnesoid X receptor signalling and decreased obesity. Nat Commun 2013; 4: 2384
    CrossrefPubMedGoogle Scholar
  • 159 Tilg H, Moschen AR. Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis. Hepatology 2010; 52 (5) 1836-1846
    CrossrefPubMedGoogle Scholar
  • 160 Mudaliar S, Henry RR, Sanyal AJ , et al. Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease. Gastroenterology 2013; 145 (3) 574-82.e1
    CrossrefPubMedGoogle Scholar
  • 161 Houten SM, Watanabe M, Auwerx J. Endocrine functions of bile acids. EMBO J 2006; 25 (7) 1419-1425
    CrossrefPubMedGoogle Scholar
  • 162 Claudel T, Sturm E, Duez H , et al. Bile acid-activated nuclear receptor FXR suppresses apolipoprotein A-I transcription via a negative FXR response element. J Clin Invest 2002; 109 (7) 961-971
    CrossrefPubMedGoogle Scholar
  • 163 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
    CrossrefPubMedGoogle Scholar
  • 164 Modica S, Gadaleta RM, Moschetta A. Deciphering the nuclear bile acid receptor FXR paradigm. Nucl Recept Signal 2010; 8: e005
    PubMedGoogle Scholar
  • 165 Fuchs M. Non-alcoholic fatty liver disease: the bile acid-activated farnesoid x receptor as an emerging treatment target. J Lipids 2012; 2012: 934396
    PubMedGoogle Scholar
  • 166 Alkhouri N, Tamimi TA, Yerian L, Lopez R, Zein NN, Feldstein AE. The inflamed liver and atherosclerosis: a link between histologic severity of nonalcoholic fatty liver disease and increased cardiovascular risk. Dig Dis Sci 2010; 55 (9) 2644-2650
    CrossrefPubMedGoogle Scholar
  • 167 Baggio LL, Drucker DJ. Biology of incretins: GLP-1 and GIP. Gastroenterology 2007; 132 (6) 2131-2157
    CrossrefPubMedGoogle Scholar
  • 168 Green JB, Bethel MA, Armstrong PW , et al; TECOS Study Group. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med 2015; 373 (3) 232-242
    CrossrefPubMedGoogle Scholar
  • 169 Carbone LJ, Angus PW, Yeomans ND. Incretin-based therapies for the treatment of nonalcoholic fatty liver disease: a systematic review and meta-analysis. J Gastroenterol Hepatol 2015;
    PubMedGoogle Scholar
  • 170 ClinicalTrials.com. 2015. Obeticholic acid. Available at: https://clinicaltrials.gov/ct2/results?term=fxr+fg . Accessed January 3, 2016
    PubMedGoogle Scholar
  • 171 Schreuder TC, Marsman HA, Lenicek M , et al. The hepatic response to FGF19 is impaired in patients with nonalcoholic fatty liver disease and insulin resistance. Am J Physiol Gastrointest Liver Physiol 2010; 298 (3) G440-G445
    CrossrefPubMedGoogle Scholar
  • 172 Alisi A, Ceccarelli S, Panera N , et al. Association between serum atypical fibroblast growth factors 21 and 19 and pediatric nonalcoholic fatty liver disease. PLoS ONE 2013; 8 (6) e67160
    CrossrefPubMedGoogle Scholar
  • 173 Gerhard GS, Styer AM, Wood GC , et al. 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
    CrossrefPubMedGoogle Scholar
  • 174 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
    CrossrefPubMedGoogle Scholar
  • 175 Miras AD, le Roux CW. Mechanisms underlying weight loss after bariatric surgery. Nat Rev Gastroenterol Hepatol 2013; 10 (10) 575-584
    CrossrefPubMedGoogle Scholar
  • 176 Ryan KK, Tremaroli V, Clemmensen C , et al. FXR is a molecular target for the effects of vertical sleeve gastrectomy. Nature 2014; 509 (7499) 183-188
    CrossrefPubMedGoogle Scholar
  • 177 Kuipers F, Groen AK. FXR: the key to benefits in bariatric surgery?. Nat Med 2014; 20 (4) 337-338
    CrossrefPubMedGoogle Scholar
  • 178 Lindor KD, Kowdley KV, Heathcote EJ , et al. Ursodeoxycholic acid for treatment of nonalcoholic steatohepatitis: results of a randomized trial. Hepatology 2004; 39 (3) 770-778
    CrossrefPubMedGoogle Scholar
  • 179 Leuschner UF, Lindenthal B, Herrmann G , et al; NASH Study Group. High-dose ursodeoxycholic acid therapy for nonalcoholic steatohepatitis: a double-blind, randomized, placebo-controlled trial. Hepatology 2010; 52 (2) 472-479
    CrossrefPubMedGoogle Scholar
  • 180 Ratziu V, de Ledinghen V, Oberti F , et al; FRESGUN. A randomized controlled trial of high-dose ursodeoxycholic acid for nonalcoholic steatohepatitis. J Hepatol 2011; 54 (5) 1011-1019
    CrossrefPubMedGoogle Scholar
  • 181 Mueller M, Thorell A, Claudel T , et al. Ursodeoxycholic acid exerts farnesoid X receptor-antagonistic effects on bile acid and lipid metabolism in morbid obesity. J Hepatol 2015; 62 (6) 1398-1404
    CrossrefPubMedGoogle Scholar
  • 182 Flowers JB, Rabaglia ME, Schueler KL , et al. Loss of stearoyl-CoA desaturase-1 improves insulin sensitivity in lean mice but worsens diabetes in leptin-deficient obese mice. Diabetes 2007; 56 (5) 1228-1239
    CrossrefPubMedGoogle Scholar
  • 183 Hulver MW, Berggren JR, Carper MJ , et al. Elevated stearoyl-CoA desaturase-1 expression in skeletal muscle contributes to abnormal fatty acid partitioning in obese humans. Cell Metab 2005; 2 (4) 251-261
    CrossrefPubMedGoogle Scholar
  • 184 Safadi R, Konikoff FM, Mahamid M , et al; FLORA Group. The fatty acid-bile acid conjugate Aramchol reduces liver fat content in patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 2014; 12 (12) 2085-91.e1
    CrossrefPubMedGoogle Scholar
  • 185 Dobrzyn P, Dobrzyn A, Miyazaki M , et al. Stearoyl-CoA desaturase 1 deficiency increases fatty acid oxidation by activating AMP-activated protein kinase in liver. Proc Natl Acad Sci U S A 2004; 101 (17) 6409-6414
    CrossrefPubMedGoogle Scholar
  • 186 Schroepfer Jr GJ. Oxysterols: modulators of cholesterol metabolism and other processes. Physiol Rev 2000; 80 (1) 361-554
    PubMedGoogle Scholar
  • 187 Joseph SB, Laffitte BA, Patel PH , et al. Direct and indirect mechanisms for regulation of fatty acid synthase gene expression by liver X receptors. J Biol Chem 2002; 277 (13) 11019-11025
    CrossrefPubMedGoogle Scholar
  • 188 Horton JD, Goldstein JL, Brown MS. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J Clin Invest 2002; 109 (9) 1125-1131
    CrossrefPubMedGoogle Scholar
  • 189 Kratzer A, Buchebner M, Pfeifer T , et al. Synthetic LXR agonist attenuates plaque formation in apoE-/- mice without inducing liver steatosis and hypertriglyceridemia. J Lipid Res 2009; 50 (2) 312-326
    PubMedGoogle Scholar
  • 190 Im SS, Osborne TF. Liver x receptors in atherosclerosis and inflammation. Circ Res 2011; 108 (8) 996-1001
    CrossrefPubMedGoogle Scholar
  • 191 Oosterveer MH, Grefhorst A, Groen AK, Kuipers F. The liver X receptor: control of cellular lipid homeostasis and beyond Implications for drug design. Prog Lipid Res 2010; 49 (4) 343-352
    CrossrefPubMedGoogle Scholar
  • 192 Grefhorst A, Elzinga BM, Voshol PJ , et al. Stimulation of lipogenesis by pharmacological activation of the liver X receptor leads to production of large, triglyceride-rich very low density lipoprotein particles. J Biol Chem 2002; 277 (37) 34182-34190
    CrossrefPubMedGoogle Scholar
  • 193 van der Veen JN, Havinga R, Bloks VW, Groen AK, Kuipers F. Cholesterol feeding strongly reduces hepatic VLDL-triglyceride production in mice lacking the liver X receptor alpha. J Lipid Res 2007; 48 (2) 337-347
    PubMedGoogle Scholar
  • 194 Inaba T, Matsuda M, Shimamura M , et al. Angiopoietin-like protein 3 mediates hypertriglyceridemia induced by the liver X receptor. J Biol Chem 2003; 278 (24) 21344-21351
    CrossrefPubMedGoogle Scholar
  • 195 Shimizugawa T, Ono M, Shimamura M , et al. ANGPTL3 decreases very low density lipoprotein triglyceride clearance by inhibition of lipoprotein lipase. J Biol Chem 2002; 277 (37) 33742-33748
    CrossrefPubMedGoogle Scholar
  • 196 Zhou J, Febbraio M, Wada T , et al. Hepatic fatty acid transporter Cd36 is a common target of LXR, PXR, and PPARgamma in promoting steatosis. Gastroenterology 2008; 134 (2) 556-567
    CrossrefPubMedGoogle Scholar
  • 197 Denechaud PD, Bossard P, Lobaccaro JM , et al. ChREBP, but not LXRs, is required for the induction of glucose-regulated genes in mouse liver. J Clin Invest 2008; 118 (3) 956-964
    PubMedGoogle Scholar
  • 198 Griffett K, Welch RD, Flaveny CA, Kolar GR, Neuschwander-Tetri BA, Burris TP. The LXR inverse agonist SR9238 suppresses fibrosis in a model of non-alcoholic steatohepatitis. Mol Metab 2015; 4 (4) 353-357
    PubMedGoogle Scholar
  • 199 Ahn SB, Jang K, Jun DW, Lee BH, Shin KJ. Expression of liver X receptor correlates with intrahepatic inflammation and fibrosis in patients with nonalcoholic fatty liver disease. Dig Dis Sci 2014; 59 (12) 2975-2982
    CrossrefPubMedGoogle Scholar
  • 200 Katz A, Udata C, Ott E , et al. Safety, pharmacokinetics, and pharmacodynamics of single doses of LXR-623, a novel liver X-receptor agonist, in healthy participants. J Clin Pharmacol 2009; 49 (6) 643-649
    CrossrefPubMedGoogle Scholar
  • 201 Ducheix S, Montagner A, Theodorou V, Ferrier L, Guillou H. The liver X receptor: a master regulator of the gut-liver axis and a target for non alcoholic fatty liver disease. Biochem Pharmacol 2013; 86 (1) 96-105
    CrossrefPubMedGoogle Scholar
  • 202 Bikle DD. Vitamin D metabolism, mechanism of action, and clinical applications. Chem Biol 2014; 21 (3) 319-329
    CrossrefPubMedGoogle Scholar
  • 203 Kwok RM, Torres DM, Harrison SA. Vitamin D and nonalcoholic fatty liver disease (NAFLD): is it more than just an association?. Hepatology 2013; 58 (3) 1166-1174
    CrossrefPubMedGoogle Scholar
  • 204 Zúñiga S, Firrincieli D, Housset C, Chignard N. Vitamin D and the vitamin D receptor in liver pathophysiology. Clin Res Hepatol Gastroenterol 2011; 35 (4) 295-302
    CrossrefPubMedGoogle Scholar
  • 205 Yin Y, Yu Z, Xia M, Luo X, Lu X, Ling W. Vitamin D attenuates high fat diet-induced hepatic steatosis in rats by modulating lipid metabolism. Eur J Clin Invest 2012; 42 (11) 1189-1196
    CrossrefPubMedGoogle Scholar
  • 206 Tiosano D, Wildbaum G, Gepstein V , et al. The role of vitamin D receptor in innate and adaptive immunity: a study in hereditary vitamin D-resistant rickets patients. J Clin Endocrinol Metab 2013; 98 (4) 1685-1693
    CrossrefPubMedGoogle Scholar
  • 207 Chang SH, Chung Y, Dong C. Vitamin D suppresses Th17 cytokine production by inducing C/EBP homologous protein (CHOP) expression. J Biol Chem 2010; 285 (50) 38751-38755
    CrossrefPubMedGoogle Scholar
  • 208 Cantorna MT, Mahon BD. Mounting evidence for vitamin D as an environmental factor affecting autoimmune disease prevalence. Exp Biol Med (Maywood) 2004; 229 (11) 1136-1142
    PubMedGoogle Scholar
  • 209 Ding N, Yu RT, Subramaniam N , et al. A vitamin D receptor/SMAD genomic circuit gates hepatic fibrotic response. Cell 2013; 153 (3) 601-613
    CrossrefPubMedGoogle Scholar
  • 210 Eliades M, Spyrou E. Vitamin D: a new player in non-alcoholic fatty liver disease?. World J Gastroenterol 2015; 21 (6) 1718-1727
    CrossrefPubMedGoogle Scholar
  • 211 Zeitz U, Weber K, Soegiarto DW, Wolf E, Balling R, Erben RG. Impaired insulin secretory capacity in mice lacking a functional vitamin D receptor. FASEB J 2003; 17 (3) 509-511
    PubMedGoogle Scholar
  • 212 Li L, Zhang L, Pan S, Wu X, Yin X. No significant association between vitamin D and nonalcoholic fatty liver disease in a Chinese population. Dig Dis Sci 2013; 58 (8) 2376-2382
    CrossrefPubMedGoogle Scholar
  • 213 Rhee E-J, Kim MK, Park SE , et al. High serum vitamin D levels reduce the risk for nonalcoholic fatty liver disease in healthy men independent of metabolic syndrome. Endocr J 2013; 60 (6) 743-752
    CrossrefPubMedGoogle Scholar
  • 214 Eliades M, Spyrou E, Agrawal N , et al. Meta-analysis: vitamin D and non-alcoholic fatty liver disease. Aliment Pharmacol Ther 2013; 38 (3) 246-254
    CrossrefPubMedGoogle Scholar
  • 215 Dasarathy J, Periyalwar P, Allampati S , et al. Hypovitaminosis D is associated with increased whole body fat mass and greater severity of non-alcoholic fatty liver disease. Liver Int 2014; 34 (6) e118-e127
    CrossrefPubMedGoogle Scholar
  • 216 Nobili V, Giorgio V, Liccardo D , et al. Vitamin D levels and liver histological alterations in children with nonalcoholic fatty liver disease. Eur J Endocrinol 2014; 170 (4) 547-553
    CrossrefPubMedGoogle Scholar
  • 217 Vaidya A, Williams JS, Forman JP. The independent association between 25-hydroxyvitamin D and adiponectin and its relation with BMI in two large cohorts: the NHS and the HPFS. Obesity (Silver Spring) 2012; 20 (1) 186-191
    CrossrefPubMedGoogle Scholar
  • 218 Autier P, Boniol M, Pizot C, Mullie P. Vitamin D status and ill health: a systematic review. Lancet Diabetes Endocrinol 2014; 2 (1) 76-89
    PubMedGoogle Scholar
  • 219 Iruzubieta P, Terán Á, Crespo J, Fábrega E. Vitamin D deficiency in chronic liver disease. World J Hepatol 2014; 6 (12) 901-915
    CrossrefPubMedGoogle Scholar
  • 220 López-Velázquez JA, Carrillo-Córdova LD, Chávez-Tapia NC, Uribe M, Méndez-Sánchez N. Nuclear receptors in nonalcoholic fatty liver disease. J Lipids 2012; 2012: 139875
    PubMedGoogle Scholar
  • 221 Chianale J, Mulholland L, Traber PG, Gumucio JJ. Phenobarbital induction of cytochrome P-450 b,e genes is dependent on protein synthesis. Hepatology 1988; 8 (2) 327-331
    CrossrefPubMedGoogle Scholar
  • 222 Nakae J, Kitamura T, Silver DL, Accili D. The forkhead transcription factor Foxo1 (Fkhr) confers insulin sensitivity onto glucose-6-phosphatase expression. J Clin Invest 2001; 108 (9) 1359-1367
    CrossrefPubMedGoogle Scholar
  • 223 Moreau A, Vilarem MJ, Maurel P, Pascussi JM. Xenoreceptors CAR and PXR activation and consequences on lipid metabolism, glucose homeostasis, and inflammatory response. Mol Pharm 2008; 5 (1) 35-41
    CrossrefPubMedGoogle Scholar
  • 224 Semple RK, Chatterjee VK, O'Rahilly S. PPAR gamma and human metabolic disease. J Clin Invest 2006; 116 (3) 581-589
    CrossrefPubMedGoogle Scholar
  • 225 Zhou J, Zhai Y, Mu Y , et al. A novel pregnane X receptor-mediated and sterol regulatory element-binding protein-independent lipogenic pathway. J Biol Chem 2006; 281 (21) 15013-15020
    CrossrefPubMedGoogle Scholar
  • 226 He J, Gao J, Xu M , et al. PXR ablation alleviates diet-induced and genetic obesity and insulin resistance in mice. Diabetes 2013; 62 (6) 1876-1887
    CrossrefPubMedGoogle Scholar
  • 227 Roth A, Looser R, Kaufmann M , et al. Regulatory cross-talk between drug metabolism and lipid homeostasis: constitutive androstane receptor and pregnane X receptor increase Insig-1 expression. Mol Pharmacol 2008; 73 (4) 1282-1289
    CrossrefPubMedGoogle Scholar
  • 228 Sookoian S, Castaño GO, Burgueño AL, Gianotti TF, Rosselli MS, Pirola CJ. The nuclear receptor PXR gene variants are associated with liver injury in nonalcoholic fatty liver disease. Pharmacogenet Genomics 2010; 20 (1) 1-8
    CrossrefPubMedGoogle Scholar
  • 229 Pascussi JM, Robert A, Nguyen M , et al. Possible involvement of pregnane X receptor-enhanced CYP24 expression in drug-induced osteomalacia. J Clin Invest 2005; 115 (1) 177-186
    CrossrefPubMedGoogle Scholar
  • 230 Lahtela JT, Arranto AJ, Sotaniemi EA. Enzyme inducers improve insulin sensitivity in non-insulin-dependent diabetic subjects. Diabetes 1985; 34 (9) 911-916
    CrossrefPubMedGoogle Scholar
  • 231 Banerjee M, Robbins D, Chen T. Targeting xenobiotic receptors PXR and CAR in human diseases. Drug Discov Today 2015; 20 (5) 618-628
    CrossrefPubMedGoogle Scholar
  • 232 Gao J, Xie W. Targeting xenobiotic receptors PXR and CAR for metabolic diseases. Trends Pharmacol Sci 2012; 33 (10) 552-558
    CrossrefPubMedGoogle Scholar
  • 233 Rysä J, Buler M, Savolainen MJ, Ruskoaho H, Hakkola J, Hukkanen J. Pregnane X receptor agonists impair postprandial glucose tolerance. Clin Pharmacol Ther 2013; 93 (6) 556-563
    CrossrefPubMedGoogle Scholar
  • 234 Wada T, Gao J, Xie W. PXR and CAR in energy metabolism. Trends Endocrinol Metab 2009; 20 (6) 273-279
    CrossrefPubMedGoogle Scholar
  • 235 Kojetin DJ, Burris TP. REV-ERB and ROR nuclear receptors as drug targets. Nat Rev Drug Discov 2014; 13 (3) 197-216
    CrossrefPubMedGoogle Scholar
  • 236 Yang J, Sundrud MS, Skepner J, Yamagata T. Targeting Th17 cells in autoimmune diseases. Trends Pharmacol Sci 2014; 35 (10) 493-500
    CrossrefPubMedGoogle Scholar
  • 237 Vonghia L, Michielsen P, Francque S. Immunological mechanisms in the pathophysiology of non-alcoholic steatohepatitis. Int J Mol Sci 2013; 14 (10) 19867-19890
    CrossrefPubMedGoogle Scholar
  • 238 Tang Y, Bian Z, Zhao L , et al. Interleukin-17 exacerbates hepatic steatosis and inflammation in non-alcoholic fatty liver disease. Clin Exp Immunol 2011; 166 (2) 281-290
    CrossrefPubMedGoogle Scholar
  • 239 Meng F, Wang K, Aoyama T , et al. Interleukin-17 signaling in inflammatory, Kupffer cells, and hepatic stellate cells exacerbates liver fibrosis in mice. Gastroenterology 2012; 143 (3) 765-76.e1 , 3
    CrossrefPubMedGoogle Scholar
  • 240 Giles DA, Moreno-Fernandez ME, Divanovic S. IL-17 axis driven inflammation in non-alcoholic fatty liver disease progression. Curr Drug Targets 2015; 16 (12) 1315-1323
    CrossrefPubMedGoogle Scholar
  • 241 Sumarac-Dumanovic M, Stevanovic D, Ljubic A , et al. Increased activity of interleukin-23/interleukin-17 proinflammatory axis in obese women. Int J Obes 2009; 33 (1) 151-156
    CrossrefPubMedGoogle Scholar
  • 242 Vonghia L, Michielsen P, Francque S. Immunological mechanisms in the pathophysiology of non-alcoholic steatohepatitis. Int J Mol Sci 2013; 14 (10) 19867-19890
    CrossrefPubMedGoogle Scholar
  • 243 Huh JR, Littman DR. Small molecule inhibitors of RORγt: targeting Th17 cells and other applications. Eur J Immunol 2012; 42 (9) 2232-2237
    CrossrefPubMedGoogle Scholar
  • 244 Monteiro R, Azevedo I. Chronic inflammation in obesity and the metabolic syndrome. Mediators Inflamm 2010; 2010
    PubMedGoogle Scholar
  • 245 Tarantino G, Costantini S, Finelli C , et al. Is serum Interleukin-17 associated with early atherosclerosis in obese patients?. J Transl Med 2014; 12: 214
    CrossrefPubMedGoogle Scholar
  • 246 Maury E, Ramsey KM, Bass J. Circadian rhythms and metabolic syndrome: from experimental genetics to human disease. Circ Res 2010; 106 (3) 447-462
    CrossrefPubMedGoogle Scholar
  • 247 Buttgereit F, Smolen JS, Coogan AN, Cajochen C. Clocking in: chronobiology in rheumatoid arthritis. Nat Rev Rheumatol 2015; 11 (6) 349-356
    CrossrefPubMedGoogle Scholar
  • 248 Innominato PF, Lévi FA, Bjarnason GA. Chronotherapy and the molecular clock: Clinical implications in oncology. Adv Drug Deliv Rev 2010; 62 (9–10) 979-1001
    CrossrefPubMedGoogle Scholar