Skip to main content

Advertisement

SpringerLink
Log in

Farnesoid X receptor as a regulator of fuel consumption and mitochondrial function

  • Review
  • Published:
Archives of Pharmacal Research Aims and scope Submit manuscript

Abstract

Maintenance of energy homeostasis is crucial for survival of organism. There exists a close link between energy metabolism and cell survival, which are coordinately regulated by common signaling pathways. Farnesoid X receptor (FXR) serves as a ligand-mediated transcription factor to regulate diverse genes involved in bile acid, lipid, and glucose metabolism, controlling cellular and systemic energy metabolism. Another important aspect on FXR biology is related to its beneficial effect on cell survival. FXR exerts antioxidative and cytoprotective effect, which is closely associated with the ability of FXR to regulate mitochondrial function. To maintain complex biological processes under homeostasis, FXR activity needs to be dynamically and tightly controlled by different signaling pathways and modifications. In this review, we discuss the role of FXR in the regulation of energy metabolism and cell survival, with the goal of understanding molecular basis for FXR regulation in physiological and pathological conditions. This information may be of assistance in understanding recent advancements of FXR research and strategies for the prevention and treatment of metabolic disorders.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  • Alasmael N, Mohan R, Meira LB, Swales KE, Plant NJ (2016) Activation of the farnesoid X-receptor in breast cancer cell lines results in cytotoxicity but not increased migration potential. Cancer Lett 370:250–259

    Article  CAS  PubMed  Google Scholar 

  • Ananthanarayanan M, Balasubramanian N, Makishima M, Mangelsdorf DJ, Suchy FJ (2001) Human bile salt export pump promoter is transactivated by the farnesoid X receptor/bile acid receptor. J Biol Chem 276:28857–28865

    Article  CAS  PubMed  Google Scholar 

  • Angelin B, Einarsson K, Hellstrom K, Leijd B (1978) Effects of cholestyramine and chenodeoxycholic acid on the metabolism of endogenous triglyceride in hyperlipoproteinemia. J Lipid Res 19:1017–1024

    CAS  PubMed  Google Scholar 

  • Balasubramaniyan N, Luo Y, Sun AQ, Suchy FJ (2013) SUMOylation of the farnesoid X receptor (FXR) regulates the expression of FXR target genes. J Biol Chem 288:13850–13862

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ballatori N, Christian WV, Lee JY, Dawson PA, Soroka CJ, Boyer JL, Madejczyk MS, Li N (2005) OSTα–OSTβ: a major basolateral bile acid and steroid transporter in human intestinal, renal, and biliary epithelia. Hepatology 42:1270–1279

    Article  CAS  PubMed  Google Scholar 

  • Bjursell M, Wedin M, Admyre T, Hermansson M, Bottcher G, Goransson M, Linden D, Bamberg K, Oscarsson J, Bohlooly YM (2013) Ageing Fxr deficient mice develop increased energy expenditure, improved glucose control and liver damage resembling NASH. PLoS One 8:e64721

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Blikslager AT, Moeser AJ, Gookin JL, Jones SL, Odle J (2007) Restoration of barrier function in injured intestinal mucosa. Physiol Rev 87:545–564

    Article  CAS  PubMed  Google Scholar 

  • Calkin AC, Tontonoz P (2012) Transcriptional integration of metabolism by the nuclear sterol-activated receptors LXR and FXR. Nat Rev Mol Cell Biol 13:213–224

    CAS  PubMed  PubMed Central  Google Scholar 

  • Cariou B, Duran-Sandoval D, Kuipers F, Staels B (2005) Farnesoid X receptor: a new player in glucose metabolism? Endocrinology 146:981–983

    Article  CAS  PubMed  Google Scholar 

  • Cariou B, van Harmelen K, Duran-Sandoval D, van Dijk TH, Grefhorst A, Abdelkarim M, Caron S, Torpier G, Fruchart JC, Gonzalez FJ, Kuipers F, Staels B (2006) The farnesoid X receptor modulates adiposity and peripheral insulin sensitivity in mice. J Biol Chem 281:11039–11049

    Article  CAS  PubMed  Google Scholar 

  • Chen W, Chiang JY (2003) Regulation of human sterol 27-hydroxylase gene (CYP27A1) by bile acids and hepatocyte nuclear factor 4α (HNF4α). Gene 313:71–82

    Article  CAS  PubMed  Google Scholar 

  • Chiang JY (2009) Bile acids: regulation of synthesis. J Lipid Res 50:1955–1966

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Claudel T, Sturm E, Duez H, Torra IP, Sirvent A, Kosykh V, Fruchart JC, Dallongeville J, Hum DW, Kuipers F, Staels B (2002) Bile acid-activated nuclear receptor FXR suppresses apolipoprotein A–I transcription via a negative FXR response element. J Clin Invest 109:961–971

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Crouse JR III (1987) Hypertriglyceridemia: a contraindication to the use of bile acid binding resins. Am J Med 83:243–248

    Article  PubMed  Google Scholar 

  • Cyphert HA, Ge X, Kohan AB, Salati LM, Zhang Y, Hillgartner FB (2012) Activation of the farnesoid X receptor induces hepatic expression and secretion of fibroblast growth factor 21. J Biol Chem 287:25123–25138

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Davis RA, Miyake JH, Hui TY, Spann NJ (2002) Regulation of cholesterol-7α-hydroxylase: BAREly missing a SHP. J Lipid Res 43:533–543

    CAS  PubMed  Google Scholar 

  • Dawson PA, Hubbert M, Haywood J, Craddock AL, Zerangue N, Christian WV, Ballatori N (2005) The heteromeric organic solute transporter α–β, Ostα–Ostβ, is an ileal basolateral bile acid transporter. J Biol Chem 280:6960–6968

    Article  CAS  PubMed  Google Scholar 

  • De Fabiani E, Mitro N, Gilardi F, Caruso D, Galli G, Crestani M (2003) Coordinated control of cholesterol catabolism to bile acids and of gluconeogenesis via a novel mechanism of transcription regulation linked to the fasted-to-fed cycle. J Biol Chem 278:39124–39132

    Article  PubMed  CAS  Google Scholar 

  • Denson LA, Sturm E, Echevarria W, Zimmerman TL, Makishima M, Mangelsdorf DJ, Karpen SJ (2001) The orphan nuclear receptor, shp, mediates bile acid-induced inhibition of the rat bile acid transporter, ntcp. Gastroenterology 121:140–147

    Article  CAS  PubMed  Google Scholar 

  • Duran-Sandoval D, Mautino G, Martin G, Percevault F, Barbier O, Fruchart JC, Kuipers F, Staels B (2004) Glucose regulates the expression of the farnesoid X receptor in liver. Diabetes 53:890–898

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fang S, Suh JM, Reilly SM, Yu E, Osborn O, Lackey D, Yoshihara E, Perino A, Jacinto S, Lukasheva Y, Atkins AR, Khvat A, Schnabl B, Yu RT (2015) Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance. Nat Med 21:159–165

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Flotho A, Melchior F (2013) Sumoylation: a regulatory protein modification in health and disease. Annu Rev Biochem 82:357–385

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Frankenberg T, Rao A, Chen F, Haywood J, Shneider BL, Dawson PA (2006) Regulation of the mouse organic solute transporter α–β, Ostα–Ostβ, by bile acids. Am J Physiol Gastrointest Liver Physiol 290:G912–G922

    Article  CAS  PubMed  Google Scholar 

  • Frankenberg T, Miloh T, Chen FY, Ananthanarayanan M, Sun AQ, Balasubramaniyan N, Arias I, Setchell KD, Suchy FJ, Shneider BL (2008) The membrane protein ATPase class I type 8B member 1 signals through protein kinase C zeta to activate the farnesoid X receptor. Hepatology 48:1896–1905

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gadaleta RM, van Erpecum KJ, Oldenburg B, Willemsen EC, Renooij W, Murzilli S, Klomp LW, Siersema PD, Schipper ME, Danese S, Penna G, Laverny G, Adorini L, Moschetta A, van Mil SW (2011) Farnesoid X receptor activation inhibits inflammation and preserves the intestinal barrier in inflammatory bowel disease. Gut 60:463–472

    Article  CAS  PubMed  Google Scholar 

  • Garcia-Rodriguez JL, Barbier-Torres L, Fernandez-Alvarez S, Gutierrez-de Juan V, Monte MJ, Halilbasic E, Herranz D, Alvarez L, Aspichueta P, Marin JJ, Trauner M, Mato JM, Serrano M, Beraza N, Martinez-Chantar ML (2014) SIRT1 controls liver regeneration by regulating bile acid metabolism through farnesoid X receptor and mammalian target of rapamycin signaling. Hepatology 59:1972–1983

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gineste R, Sirvent A, Paumelle R, Helleboid S, Aquilina A, Darteil R, Hum DW, Fruchart JC, Staels B (2008) Phosphorylation of farnesoid X receptor by protein kinase C promotes its transcriptional activity. Mol Endocrinol 22:2433–2447

    Article  CAS  PubMed  Google Scholar 

  • Glass CK, Rosenfeld MG (2000) The coregulator exchange in transcriptional functions of nuclear receptors. Genes Dev 14:121–141

    CAS  PubMed  Google Scholar 

  • Gomez-Ospina N, Potter CJ, Xiao R, Manickam K, Kim MS, Kim KH, Shneider BL, Picarsic JL, Jacobson TA, Zhang J, He W, Liu P, Knisely AS, Finegold MJ, Muzny DM, Boerwinkle E, Lupski JR, Plon SE, Gibbs RA, Eng CM, Yang Y, Washington GC, Porteus MH, Berquist WE, Kambham N, Singh RJ, Xia F, Enns GM, Moore DD (2016) Mutations in the nuclear bile acid receptor FXR cause progressive familial intrahepatic cholestasis. Nat Commun 7:10713

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Goodwin B, Jones SA, Price RR, Watson MA, McKee DD, Moore LB, Galardi C, Wilson JG, Lewis MC, Roth ME, Maloney PR, Willson TM, Kliewer SA (2000) A regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis. Mol Cell 6:517–526

    Article  CAS  PubMed  Google Scholar 

  • Grober J, Zaghini I, Fujii H, Jones SA, Kliewer SA, Willson TM, Ono T, Besnard P (1999) Identification of a bile acid-responsive element in the human ileal bile acid-binding protein gene. Involvement of the farnesoid X receptor/9-cis-retinoic acid receptor heterodimer. J Biol Chem 274:29749–29754

    Article  CAS  PubMed  Google Scholar 

  • Guo F, Xu Z, Zhang Y, Jiang P, Huang G, Chen S, Lyu X, Zheng P, Zhao X, Zeng Y, Wang S, He F (2015) FXR induces SOCS3 and suppresses hepatocellular carcinoma. Oncotarget 6:34606–34616

    PubMed  PubMed Central  Google Scholar 

  • He J, Zhao K, Zheng L, Xu Z, Gong W, Chen S, Shen X, Huang G, Gao M, Zeng Y, Zhang Y, He F (2015) Upregulation of microRNA-122 by farnesoid X receptor suppresses the growth of hepatocellular carcinoma cells. Mol Cancer 14:163

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Henriksen EJ, Dokken BB (2006) Role of glycogen synthase kinase-3 in insulin resistance and type 2 diabetes. Curr Drug Targets 7:1435–1441

    Article  CAS  PubMed  Google Scholar 

  • Hill BG, Benavides GA, Lancaster JR Jr, Ballinger S, Dell’Italia L, Jianhua Z, Darley-Usmar VM (2012) Integration of cellular bioenergetics with mitochondrial quality control and autophagy. Biol Chem 393:1485–1512

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hu X, Zhang Q, Zheng J, Kong W, Zhang HH, Zeng TS, Zhang JY, Min J, Wu C, Chen LL (2016) Alteration of FXR phosphorylation and sumoylation in liver in the development of adult catch-up growth. Exp Biol Med (Maywood). doi:10.1177/1535370216641788

    Google Scholar 

  • Huber RM, Murphy K, Miao B, Link JR, Cunningham MR, Rupar MJ, Gunyuzlu PL, Haws TF, Kassam A, Powell F, Hollis GF, Young PR, Mukherjee R, Burn TC (2002) Generation of multiple farnesoid-X-receptor isoforms through the use of alternative promoters. Gene 290:35–43

    Article  CAS  PubMed  Google Scholar 

  • Ijssennagger N, Janssen AW, Milona A, Ramos Pittol JM, Hollman DA, Mokry M, Betzel B, Berends FJ, Janssen IM, van Mil SW, Kersten S (2016) Gene expression profiling in human precision cut liver slices in response to the FXR agonist obeticholic acid. J Hepatol 64:1158–1166

    Article  CAS  PubMed  Google Scholar 

  • Inagaki T, Choi M, Moschetta A, Peng L, Cummins CL, McDonald JG, Luo G, Jones SA, Goodwin B, Richardson JA, Gerard RD, Repa JJ, Mangelsdorf DJ, Kliewer SA (2005) Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis. Cell Metab 2:217–225

    Article  CAS  PubMed  Google Scholar 

  • Inagaki T, Moschetta A, Lee YK, Peng L, Zhao G, Downes M, Yu RT, Shelton JM, Richardson JA, Repa JJ, Mangelsdorf DJ, Kliewer SA (2006) Regulation of antibacterial defense in the small intestine by the nuclear bile acid receptor. Proc Natl Acad Sci USA 103:3920–3925

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jung EH, Lee JH, Kim SC, Kim YW (2015) AMPK activation by liquiritigenin inhibited oxidative hepatic injury and mitochondrial dysfunction induced by nutrition deprivation as mediated with induction of farnesoid X receptor. Eur J Nutr. doi:10.1007/s00394-015-1107-7

    Google Scholar 

  • Kast HR, Goodwin B, Tarr PT, Jones SA, Anisfeld AM, Stoltz CM, Tontonoz P, Kliewer S, Willson TM, Edwards PA (2002) Regulation of multidrug resistance-associated protein 2 (ABCC2) by the nuclear receptors pregnane X receptor, farnesoid X-activated receptor, and constitutive androstane receptor. J Biol Chem 277:2908–2915

    Article  CAS  PubMed  Google Scholar 

  • Kaur J, Debnath J (2015) Autophagy at the crossroads of catabolism and anabolism. Nat Rev Mol Cell Biol 16:461–472

    Article  CAS  PubMed  Google Scholar 

  • Kawata K, Kobayashi Y, Souda K, Kawamura K, Sumiyoshi S, Takahashi Y, Noritake H, Watanabe S, Suehiro T, Nakamura H (2010) Enhanced hepatic Nrf2 activation after ursodeoxycholic acid treatment in patients with primary biliary cirrhosis. Antioxid Redox Signal 13:259–268

    Article  CAS  PubMed  Google Scholar 

  • Kay HY, Kim WD, Hwang SJ, Choi HS, Gilroy RK, Wan YJ, Kim SG (2011) Nrf2 inhibits LXRα-dependent hepatic lipogenesis by competing with FXR for acetylase binding. Antioxid Redox Signal 15:2135–2146

    Article  CAS  PubMed  Google Scholar 

  • Kemper JK, Xiao Z, Ponugoti B, Miao J, Fang S, Kanamaluru D, Tsang S, Wu SY, Chiang CM, Veenstra TD (2009) FXR acetylation is normally dynamically regulated by p300 and SIRT1 but constitutively elevated in metabolic disease states. Cell Metab 10:392–404

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim DH, Xiao Z, Kwon S, Sun X, Ryerson D, Tkac D, Ma P, Wu SY, Chiang CM, Zhou E, Xu HE, Palvimo JJ, Chen LF, Kemper B, Kemper JK (2015) A dysregulated acetyl/SUMO switch of FXR promotes hepatic inflammation in obesity. EMBO J 34:184–199

    Article  PubMed  CAS  Google Scholar 

  • Kurosu H, Choi M, Ogawa Y, Dickson AS, Goetz R, Eliseenkova AV, Mohammadi M, Rosenblatt KP, Kliewer SA, Kuro-o M (2007) Tissue-specific expression of βKlotho and fibroblast growth factor (FGF) receptor isoforms determines metabolic activity of FGF19 and FGF21. J Biol Chem 282:26687–26695

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Landrier JF, Grober J, Zaghini I, Besnard P (2002) Regulation of the ileal bile acid-binding protein gene: an approach to determine its physiological function(s). Mol Cell Biochem 239:149–155

    Article  CAS  PubMed  Google Scholar 

  • Lee J, Kim MS (2007) The role of GSK3 in glucose homeostasis and the development of insulin resistance. Diabetes Res Clin Pract 77(Suppl 1):S49–S57

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Lee FY, de Aguiar Vallim TQ, Chong HK, Zhang Y, Liu Y, Jones SA, Osborne TF, Edwards PA (2010) Activation of the farnesoid X receptor provides protection against acetaminophen-induced hepatic toxicity. Mol Endocrinol 24:1626–1636

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee CG, Kim YW, Kim EH, Meng Z, Huang W, Hwang SJ, Kim SG (2012a) Farnesoid X receptor protects hepatocytes from injury by repressing miR-199a-3p, which increases levels of LKB1. Gastroenterology 142:1206–1217

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee J, Giordano S, Zhang J (2012b) Autophagy, mitochondria and oxidative stress: cross-talk and redox signalling. Biochem J 441:523–540

    Article  CAS  PubMed  Google Scholar 

  • Lee J, Seok S, Yu P, Kim K, Smith Z, Rivas-Astroza M, Zhong S, Kemper JK (2012c) Genomic analysis of hepatic farnesoid X receptor binding sites reveals altered binding in obesity and direct gene repression by farnesoid X receptor in mice. Hepatology 56:108–117

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee JM, Wagner M, Xiao R, Kim KH, Feng D, Lazar MA, Moore DD (2014) Nutrient-sensing nuclear receptors coordinate autophagy. Nature 516:112–115

    CAS  PubMed  PubMed Central  Google Scholar 

  • Li H, Chen F, Shang Q, Pan L, Shneider BL, Chiang JY, Forman BM, Ananthanarayanan M, Tint GS, Salen G, Xu G (2005) FXR-activating ligands inhibit rabbit ASBT expression via FXR-SHP-FTF cascade. Am J Physiol Gastrointest Liver Physiol 288:G60–G66

    Article  CAS  PubMed  Google Scholar 

  • Lien F, Berthier A, Bouchaert E, Gheeraert C, Alexandre J, Porez G, Prawitt J, Dehondt H, Ploton M, Colin S, Lucas A, Patrice A, Pattou F, Diemer H, Van Dorsselaer A, Rachez C, Kamilic J, Groen AK, Staels B, Lefebvre P (2014) Metformin interferes with bile acid homeostasis through AMPK–FXR crosstalk. J Clin Invest 124:1037–1051

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu Y, Binz J, Numerick MJ, Dennis S, Luo G, Desai B, MacKenzie KI, Mansfield TA, Kliewer SA, Goodwin B, Jones SA (2003) Hepatoprotection by the farnesoid X receptor agonist GW4064 in rat models of intra- and extrahepatic cholestasis. J Clin Invest 112:1678–1687

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu X, Zhang X, Ji L, Gu J, Zhou M, Chen S (2015) Farnesoid X receptor associates with β-catenin and inhibits its activity in hepatocellular carcinoma. Oncotarget 6:4226–4238

    Article  PubMed  PubMed Central  Google Scholar 

  • Livero FA, Stolf AM, Dreifuss AA, Bastos-Pereira AL, Chicorski R, de Oliveira LG, de Souza CE, Fabossi IA, Rabitto IS, Gremski LH, Henneberg R, Telles JE, Oude Elferink RP, Acco A (2014) The FXR agonist 6ECDCA reduces hepatic steatosis and oxidative stress induced by ethanol and low-protein diet in mice. Chem Biol Interact 217:19–27

    Article  CAS  PubMed  Google Scholar 

  • Lu Y, Ma Z, Zhang Z, Xiong X, Wang X, Zhang H, Shi G, Xia X, Ning G, Li X (2014) Yin Yang 1 promotes hepatic steatosis through repression of farnesoid X receptor in obese mice. Gut 63:170–178

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mak PA, Kast-Woelbern HR, Anisfeld AM, Edwards PA (2002) Identification of PLTP as an LXR target gene and apoE as an FXR target gene reveals overlapping targets for the two nuclear receptors. J Lipid Res 43:2037–2041

    Article  CAS  PubMed  Google Scholar 

  • Manley S, Ni HM, Kong B, Apte U, Guo G, Ding WX (2014a) Suppression of autophagic flux by bile acids in hepatocytes. Toxicol Sci 137:478–490

    Article  CAS  PubMed  Google Scholar 

  • Manley S, Ni HM, Williams JA, Kong B, DiTacchio L, Guo G, Ding WX (2014b) Farnesoid X receptor regulates forkhead Box O3a activation in ethanol-induced autophagy and hepatotoxicity. Redox Biol 2c:991–1002

    Article  CAS  Google Scholar 

  • Mudaliar S, Henry RR, Sanyal AJ, Morrow L, Marschall HU, Kipnes M, Adorini L, Sciacca CI, Clopton P, Castelloe E, Dillon P, Pruzanski M, Shapiro D (2013) Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease. Gastroenterology 145:574–582

    Article  CAS  PubMed  Google Scholar 

  • Neimark E, Chen F, Li X, Shneider BL (2004) Bile acid-induced negative feedback regulation of the human ileal bile acid transporter. Hepatology 40:149–156

    Article  CAS  PubMed  Google Scholar 

  • Noh K, Kim YM, Kim YW, Kim SG (2011) Farnesoid X receptor activation by chenodeoxycholic acid induces detoxifying enzymes through AMP-activated protein kinase and extracellular signal-regulated kinase 1/2-mediated phosphorylation of CCAAT/enhancer binding protein β. Drug Metab Dispos 39:1451–1459

    Article  CAS  PubMed  Google Scholar 

  • Okada K, Shoda J, Taguchi K, Maher JM, Ishizaki K, Inoue Y, Ohtsuki M, Goto N, Takeda K, Utsunomiya H, Oda K, Warabi E, Ishii T, Osaka K, Hyodo I, Yamamoto M (2008) Ursodeoxycholic acid stimulates Nrf2-mediated hepatocellular transport, detoxification, and antioxidative stress systems in mice. Am J Physiol Gastrointest Liver Physiol 295:G735–G747

    Article  CAS  PubMed  Google Scholar 

  • 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, Paabo S, Mous J, Kremoser C, Deuschle U (2003) Identification of farnesoid X receptor β as a novel mammalian nuclear receptor sensing lanosterol. Mol Cell Biol 23:864–872

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pineda Torra I, Claudel T, Duval C, Kosykh V, Fruchart JC, Staels B (2003) Bile acids induce the expression of the human peroxisome proliferator-activated receptor alpha gene via activation of the farnesoid X receptor. Mol Endocrinol 17:259–272

    Article  PubMed  CAS  Google Scholar 

  • Pu J, Yuan A, Shan P, Gao E, Wang X, Wang Y, Lau WB, Koch W, Ma XL, He B (2013) Cardiomyocyte-expressed farnesoid-X-receptor is a novel apoptosis mediator and contributes to myocardial ischaemia/reperfusion injury. Eur Heart J 34:1834–1845

    Article  CAS  PubMed  Google Scholar 

  • Pullinger CR, Eng C, Salen G, Shefer S, Batta AK, Erickson SK, Verhagen A, Rivera CR, Mulvihill SJ, Malloy MJ, Kane JP (2002) Human cholesterol 7α-hydroxylase (CYP7A1) deficiency has a hypercholesterolemic phenotype. J Clin Invest 110:109–117

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Sanyal S, Bavner A, Haroniti A, Nilsson LM, Lundasen T, Rehnmark S, Witt MR, Einarsson C, Talianidis I, Gustafsson JA, Treuter E (2007) Involvement of corepressor complex subunit GPS2 in transcriptional pathways governing human bile acid biosynthesis. Proc Natl Acad Sci USA 104:15665–15670

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Savkur RS, Bramlett KS, Michael LF, Burris TP (2005) Regulation of pyruvate dehydrogenase kinase expression by the farnesoid X receptor. Biochem Biophys Res Commun 329:391–396

    Article  CAS  PubMed  Google Scholar 

  • Seok S, Fu T, Choi SE, Li Y, Zhu R, Kumar S, Sun X, Yoon G, Kang Y, Zhong W, Ma J, Kemper B, Kemper JK (2014) Transcriptional regulation of autophagy by an FXR-CREB axis. Nature 516:108–111

    CAS  PubMed  PubMed Central  Google Scholar 

  • Seol W, Choi HS, Moore DD (1996) An orphan nuclear hormone receptor that lacks a DNA binding domain and heterodimerizes with other receptors. Science 272:1336–1339

    Article  CAS  PubMed  Google Scholar 

  • Sinal CJ, Tohkin M, Miyata M, Ward JM, Lambert G, Gonzalez FJ (2000) Targeted disruption of the nuclear receptor FXR/BAR impairs bile acid and lipid homeostasis. Cell 102:731–744

    Article  CAS  PubMed  Google Scholar 

  • Stayrook KR, Bramlett KS, Savkur RS, Ficorilli J, Cook T, Christe ME, Michael LF, Burris TP (2005) Regulation of carbohydrate metabolism by the farnesoid X receptor. Endocrinology 146:984–991

    Article  CAS  PubMed  Google Scholar 

  • Su H, Ma C, Liu J, Li N, Gao M, Huang A, Wang X, Huang W, Huang X (2012) Downregulation of nuclear receptor FXR is associated with multiple malignant clinicopathological characteristics in human hepatocellular carcinoma. Am J Physiol Gastrointest Liver Physiol 303:G1245–G1253

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tan KP, Yang M, Ito S (2007) Activation of nuclear factor (erythroid-2 like) factor 2 by toxic bile acids provokes adaptive defense responses to enhance cell survival at the emergence of oxidative stress. Mol Pharmacol 72:1380–1390

    Article  CAS  PubMed  Google Scholar 

  • Urquhart BL, Tirona RG, Kim RB (2007) Nuclear receptors and the regulation of drug-metabolizing enzymes and drug transporters: implications for interindividual variability in response to drugs. J Clin Pharmacol 47:566–578

    Article  CAS  PubMed  Google Scholar 

  • van Waarde WM, Verkade HJ, Wolters H, Havinga R, Baller J, Bloks V, Muller M, Sauer PJ, Kuipers F (2002) Differential effects of streptozotocin-induced diabetes on expression of hepatic ABC-transporters in rats. Gastroenterology 122:1842–1852

    Article  PubMed  CAS  Google Scholar 

  • Vaquero J, Briz O, Herraez E, Muntane J, Marin JJ (2013) Activation of the nuclear receptor FXR enhances hepatocyte chemoprotection and liver tumor chemoresistance against genotoxic compounds. Biochim Biophys Acta 1833:2212–2219

    Article  CAS  PubMed  Google Scholar 

  • Vavassori P, Mencarelli A, Renga B, Distrutti E, Fiorucci S (2009) The bile acid receptor FXR is a modulator of intestinal innate immunity. J Immunol 183:6251–6261

    Article  CAS  PubMed  Google Scholar 

  • Wang YD, Chen WD, Wang M, Yu D, Forman BM, Huang W (2008) Farnesoid X receptor antagonizes nuclear factor kappaB in hepatic inflammatory response. Hepatology 48:1632–1643

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang YD, Chen WD, Li C, Guo C, Li Y, Qi H, Shen H, Kong J, Long X, Yuan F, Wang X, Huang W (2015) Farnesoid X receptor antagonizes JNK signaling pathway in liver carcinogenesis by activating SOD3. Mol Endocrinol 29:322–331

    Article  PubMed  CAS  Google Scholar 

  • Wang W, Zhan M, Li Q, Chen W, Chu H, Huang Q, Hou Z, Man M, Wang J (2016) FXR agonists enhance the sensitivity of biliary tract cancer cells to cisplatin via SHP dependent inhibition of Bcl-xL expression. Oncotarget. doi:10.18632/oncotarget.8964

    Google Scholar 

  • Watanabe M, Houten SM, Wang L, Moschetta A, Mangelsdorf DJ, Heyman RA, Moore DD, Auwerx J (2004) Bile acids lower triglyceride levels via a pathway involving FXR, SHP, and SREBP-1c. J Clin Invest 113:1408–1418

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Watanabe M, Horai Y, Houten SM, Morimoto K, Sugizaki T, Arita E, Mataki C, Sato H, Tanigawara Y, Schoonjans K, Itoh H, Auwerx J (2011) Lowering bile acid pool size with a synthetic farnesoid X receptor (FXR) agonist induces obesity and diabetes through reduced energy expenditure. J Biol Chem 286:26913–26920

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Williams JA, Thomas AM, Li G, Kong B, Zhan L, Inaba Y, Xie W, Ding WX, Guo GL (2012) Tissue specific induction of p62/Sqstm1 by farnesoid X receptor. PLoS One 7:e43961

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wolfe A, Thomas A, Edwards G, Jaseja R, Guo GL, Apte U (2011) Increased activation of the Wnt/β-catenin pathway in spontaneous hepatocellular carcinoma observed in farnesoid X receptor knockout mice. J Pharmacol Exp Ther 338:12–21

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wu WB, Xu YY, Cheng WW, Wang YX, Liu Y, Huang D, Zhang HJ (2015) Agonist of farnesoid X receptor protects against bile acid induced damage and oxidative stress in mouse placenta—a study on maternal cholestasis model. Placenta 36:545–551

    Article  PubMed  CAS  Google Scholar 

  • Yamagata K, Daitoku H, Shimamoto Y, Matsuzaki H, Hirota K, Ishida J, Fukamizu A (2004) Bile acids regulate gluconeogenic gene expression via small heterodimer partner-mediated repression of hepatocyte nuclear factor 4 and Foxo1. J Biol Chem 279:23158–23165

    Article  CAS  PubMed  Google Scholar 

  • Yang Y, Zhang M, Eggertsen G, Chiang JY (2002) On the mechanism of bile acid inhibition of rat sterol 12α-hydroxylase gene (CYP8B1) transcription: roles of α-fetoprotein transcription factor and hepatocyte nuclear factor 4α. Biochim Biophys Acta 1583:63–73

    Article  CAS  PubMed  Google Scholar 

  • Yao J, Zhou CS, Ma X, Fu BQ, Tao LS, Chen M, Xu YP (2014) FXR agonist GW4064 alleviates endotoxin-induced hepatic inflammation by repressing macrophage activation. World J Gastroenterol 20:14430–14441

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Zhang Y, Kast-Woelbern HR, Edwards PA (2003) Natural structural variants of the nuclear receptor farnesoid X receptor affect transcriptional activation. J Biol Chem 278:104–110

    Article  CAS  PubMed  Google Scholar 

  • Zhang Y, Castellani LW, Sinal CJ, Gonzalez FJ, Edwards PA (2004) Peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC-1α) regulates triglyceride metabolism by activation of the nuclear receptor FXR. Genes Dev 18:157–169

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang Y, Lee FY, Barrera G, Lee H, Vales C, Gonzalez FJ, Willson TM, Edwards PA (2006) Activation of the nuclear receptor FXR improves hyperglycemia and hyperlipidemia in diabetic mice. Proc Natl Acad Sci USA 103:1006–1011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang S, Liu Q, Wang J, Harnish DC (2009a) Suppression of interleukin-6-induced C-reactive protein expression by FXR agonists. Biochem Biophys Res Commun 379:476–479

    Article  CAS  PubMed  Google Scholar 

  • Zhang S, Wang J, Liu Q, Harnish DC (2009b) Farnesoid X receptor agonist WAY-362450 attenuates liver inflammation and fibrosis in murine model of non-alcoholic steatohepatitis. J Hepatol 51:380–388

    Article  CAS  PubMed  Google Scholar 

  • Zhang Y, Gong W, Dai S, Huang G, Shen X, Gao M, Xu Z, Zeng Y, He F (2012) Downregulation of human farnesoid X receptor by miR-421 promotes proliferation and migration of hepatocellular carcinoma cells. Mol Cancer Res 10:516–522

    Article  CAS  PubMed  Google Scholar 

  • Zollner G, Fickert P, Fuchsbichler A, Silbert D, Wagner M, Arbeiter S, Gonzalez FJ, Marschall HU, Zatloukal K, Denk H, Trauner M (2003) Role of nuclear bile acid receptor, FXR, in adaptive ABC transporter regulation by cholic and ursodeoxycholic acid in mouse liver, kidney and intestine. J Hepatol 39:480–488

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by a fund from Korea Institute of Oriental Medicine (K16820) and the Bio and Medical Technology Development Program of the NRF Funded by the Korean government, MSIP (2015M3A9B6074045).

Author information

Author notes

    Authors and Affiliations

    1. College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea

      Chang Yeob Han, Tae Hyun Kim, Ja Hyun Koo & Sang Geon Kim

    Authors
    1. Chang Yeob Han
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Tae Hyun Kim
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Ja Hyun Koo
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Sang Geon Kim
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to Sang Geon Kim.

    Ethics declarations

    Conflict of interest

    The authors declare that they have no conflict of interest.

    Additional information

    Chang Yeob Han and Tae Hyun Kim have contributed equally to this work.

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Han, C.Y., Kim, T.H., Koo, J.H. et al. Farnesoid X receptor as a regulator of fuel consumption and mitochondrial function. Arch. Pharm. Res. 39, 1062–1074 (2016). https://doi.org/10.1007/s12272-016-0812-y

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s12272-016-0812-y

    Keywords

    Search

    Navigation