Journal List > J Korean Endocr Soc > v.23(3) > 1003429

Lee and Park: Metabolic Regulation of Nuclear Receptors

Figures and Tables

Fig. 1
Nuclear receptors as ligand-dependent transcription factors. A. the structure of the nuclear receptor : N-terminal activation function 1 (AF1), DNA binding, ligand binding, and C-terminal AF2 domains. B. Response elements in the nuclear receptor can be configured as either direct, inverted, or everted repeats of the hexad core sequence AGGTCA. The number of nucleotides between the two core elements (n) confers additional specificity. C. RXR heterodimers constitutively bind to response elements in the promoter regions of target genes.
Fig. 2
Metabolic regulation by thyroid hormone receptor (TR).
Fig. 3
Metabolic regulation by peroxisome proliferator-activated receptor (PPAR).
Fig. 4
Metabolic regulation by Liver X receptor (LXR).
Fig. 5
Metabolic regulation by farnesoid X receptor (FXR).
Fig. 6
Metabolic regulation by pregnane X receptor (PXR) and constitutive androstane receptor (CAR).
Fig. 7
Metabolic regulation by small heterodimer partner (SHP)
Table 1
Classification of Nuclear Receptors

NR, nuclear receptor; GR, glucocorticoid receptor; MR, mineralocorticoid receptor; PR, progesteron receptor; AR, androgen receptor; ER, estrogen receptor; TR, thyroid hormone receptor; RAR, retinoic acid receptor; VDR, vitamin D receptor; RXR, retinoid X receptor; PPAR, peroxisome proliferator-activated receptor; LXR, liver X receptor; FXR, farnesoid X receptor; PXR, pregnane X receptor; CAR, constitutive androstane receptor; HNF-4, hepatocyte nuclear receptor-4; ROR, retinoid-related orphan receptor; ERR, estrogen related receptor; SHP, small heterodimer partner; DAX-1, Dosage-sensitive sex reversal-adrenal hypoplasia congenita critical region on the X chromosome, gene 1; TLX, Tailless homolog; PNR, Photoreceptor-specific nuclear receptor; GCNF, Germ cell nuclear factor 1; COUP-TFII, Chicken ovalbumin upstream promoter transcription factor II.

Table 2
Nuclear Receptors Associated with Metabolic Disease, and Their Synthetic Ligands

GR, glucocorticoid receptor; TR, thyroid hormone receptor; PPAR, peroxisome proliferator-activated receptor; LXR, liver X receptor; FXR, farnesoid X receptor; PXR, pregnane X receptor; CAR, constitutive androstane receptor; SHP, small heterodimer partner.


1. Grundy SM, Brewer HB Jr, Cleeman JI, Smith SC Jr, Lenfant C. Definition of metabolic syndrome: Report of the National Heart, Lung, and Blood Institute/American Heart Association conference on scientific issues related to definition. Circulation. 2004. 109:433–438.
2. Lakka HM, Laaksonen DE, Lakka TA, Niskanen LK, Kumpusalo E, Tuomilehto J, Salonen JT. The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA. 2002. 288:2709–2716.
3. Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. JAMA. 2002. 287:356–359.
4. Park MJ, Yun KE, Lee GE, Cho HJ, Park HS. A cross-sectional study of socioeconomic status and the metabolic syndrome in Korean adults. Ann Epidemiol. 2007. 17:320–326.
5. Hollenberg SM, Weinberger C, Ong ES, Cerelli G, Oro A, Lebo R, Thompson EB, Rosenfeld MG, Evans RM. Primary structure and expression of a functional human glucocorticoid receptor cDNA. Nature. 1985. 318:635–641.
6. Sonoda J, Pei L, Evans RM. Nuclear receptors: decoding metabolic disease. FEBS Lett. 2008. 582:2–9.
7. Glass CK. Differential recognition of target genes by nuclear receptor monomers, dimers, and heterodimers. Endocr Rev. 1994. 15:391–407.
8. Walker BR, Andrew R. Tissue production of cortisol by 11beta-hydroxysteroid dehydrogenase type 1 and metabolic disease. Ann N Y Acad Sci. 2006. 1083:165–184.
9. Duntas LH, Wartofsky L. Cardiovascular risk and subclinical hypothyroidism: focus on lipids and new emerging risk factors. What is the evidence? Thyroid. 2007. 17:1075–1084.
10. Grover GJ, Mellstrom K, Ye L, Malm J, Li YL, Bladh LG, Sleph PG, Smith MA, George R, Vennstrom B, Mookhtiar K, Horvath R, Speelman J, Egan D, Baxter JD. Selective thyroid hormone receptor-beta activation: a strategy for reduction of weight, cholesterol, and lipoprotein (a) with reduced cardiovascular liability. Proc Natl Acad Sci USA. 2003. 100:10067–10072.
11. Moreno M, de Lange P, Lombardi A, Silvestri E, Lanni A, Goglia F. Metabolic effects of thyroid hormone derivatives. Thyroid. 2008. 18:239–253.
12. Cappola AR, Ladenson PW. Hypothyroidism and atherosclerosis. J Clin Endocrinol Metab. 2003. 88:2438–2444.
13. Erion MD, Cable EE, Ito BR, Jiang H, Fujitaki JM, Finn PD, Zhang BH, Hou J, Boyer SH, van Poelje PD, Linemeyer DL. Targeting thyroid hormone receptor-beta agonists to the liver reduces cholesterol and triglycerides and improves the therapeutic index. Proc Natl Acad Sci USA. 2007. 104:15490–15495.
14. Shulman AI, Mangelsdorf DJ. Retinoid X receptor heterodimers in the metabolic syndrome. N Engl J Med. 2005. 353:604–615.
15. Bosse Y, Despres JP, Bouchard C, Perusse L, Vohl MC. The peroxisome proliferator-activated receptor alpha L162V mutation is associated with reduced adiposity. Obes Res. 2003. 11:809–816.
16. Muise ES, Azzolina B, Kuo DW, El-Sherbeini M, Tan Y, Yuan X, Mu J, Thompson JR, Berger JP, Wong KK. Adipose fibroblast growth factor 21 is up-regulated by PPARγ and altered metabolic states. Mol Pharmacol. 2008. [Epub ahead of print].
17. Chawla A, Lee CH, Barak Y, He W, Rosenfeld J, Liao D, Han J, Kang H, Evans RM. PPARdelta is a very low-density lipoprotein sensor in macrophages. Proc Natl Acad Sci USA. 2003. 100:1268–1273.
18. Oliver WR Jr, Shenk JL, Snaith MR, Russell CS, Plunket KD, Bodkin NL, Lewis MC, Winegar DA, Sznaidman ML, Lambert MH, Xu HE, Sternbach DD, Kliewer SA, Hansen BC, Willson TM. A selective peroxisome proliferator-activated receptor delta agonist promotes reverse cholesterol transport. Proc Natl Acad Sci USA. 2001. 98:5306–5311.
19. Mitro N, Mak PA, Vargas L, Godio C, Hampton E, Molteni V, Kreusch A, Saez E. The nuclear receptor LXR is a glucose sensor. Nature. 2007. 445:219–223.
20. Torra IP, Ismaili N, Feig JE, Xu CF, Cavasotto C, Pancratov R, Rogatsky I, Neubert TA, Fisher EA, Garabedian MJ. Phosphorylation of liver X receptor alpha selectively regulates target gene expression in macrophages. Mol Cell Biol. 2008. 28:2626–2636.
21. Nomiyama T, Bruemmer D. Liver X receptors as therapeutic targets in metabolism and atherosclerosis. Curr Atheroscler Rep. 2008. 10:88–95.
22. Makishima M, Okamoto AY, Repa JJ, Tu H, Learned RM, Luk A, Hull MV, Lustig KD, Mangelsdorf DJ, Shan B. Identification of a nuclear receptor for bile acids. Science. 1999. 284:1362–1365.
23. Ananthanarayanan M, Balasubramanian N, Makishima M, Mangelsdorf DJ, Suchy FJ. Human bile salt export pump promoter is transactivated by the farnesoid X receptor/bile acid receptor. J Biol Chem. 2001. 276:28857–28865.
24. de Wit NJ, Bosch-Vermeulen H, de Groot PJ, Hooiveld GJ, Grootte Bromhaar MM, Jansen J, Muller M, van der Meer R. The role of the small intestine in the development of dietary fat-induced obesity and insulin resistance in C57BL/6J mice. BMC Med Genomics. 2008. 1:14.
25. Watanabe M, Houten SM, Wang L, Moschetta A, Mangelsdorf DJ, Heyman RA, Moore DD, Auwerx J. Bile acids lower triglyceride levels via a pathway involving FXR, SHP, and SREBP-1c. J Clin Invest. 2004. 113:1408–1418.
26. Cynamon HA, Andres JM, Iafrate RP. Rifampin relieves pruritus in children with cholestatic liver disease. Gastroenterology. 1990. 98:1013–1016.
27. Konno Y, Negishi M, Kodama S. The roles of nuclear receptors CAR and PXR in hepatic energy metabolism. Drug Metab Pharmacokinet. 2008. 23:8–13.
28. Lahtela JT, Arranto AJ, Sotaniemi EA. Enzyme inducers improve insulin sensitivity in non-insulin-dependent diabetic subjects. Diabetes. 1985. 34:911–916.
29. Kodama S, Koike C, Negishi M, Yamamoto Y. Nuclear receptors CAR and PXR cross talk with FOXO1 to regulate genes that encode drug-metabolizing and gluconeogenic enzymes. Mol Cell Biol. 2004. 24:7931–7940.
30. Zhang W, Patil S, Chauhan B, Guo S, Powell DR, Le J, Klotsas A, Matika R, Xiao X, Franks R, Heidenreich KA, Sajan MP, Farese RV, Stolz DB, Tso P, Koo SH, Montminy M, Unterman TG. FoxO1 regulates multiple metabolic pathways in the liver: effects on gluconeogenic, glycolytic, and lipogenic gene expression. J Biol Chem. 2006. 281:10105–10117.
31. Shin DJ, Osborne TF. PGC-1alpha activation of CYP7A1 during food restriction and diabetes is still inhibited by small heterodimer partner. J Biol Chem. 2008. 283:15089–15096.
32. Lee YS, Chanda D, Sim J, Park YY, Choi HS. Structure and function of the atypical orphan nuclear receptor small heterodimer partner. Int Rev Cytol. 2007. 261:117–158.
33. Odom DT, Zizlsperger N, Gordon DB, Bell GW, Rinaldi NJ, Murray HL, Volkert TL, Schreiber J, Rolfe PA, Gifford DK, Fraenkel E, Bell GI, Young RA. Control of pancreas and liver gene expression by HNF transcription factors. Science. 2004. 303:1378–1381.
34. Ma K, Saha PK, Chan L, Moore DD. Farnesoid X receptor is essential for normal glucose homeostasis. J Clin Invest. 2006. 116:1102–1109.
35. Wang L, Huang J, Saha P, Kulkarni RN, Hu M, Kim Y, Park K, Chan L, Rajan AS, Lee I, Moore DD. Orphan receptor small heterodimer partner is an important mediator of glucose homeostasis. Mol Endocrinol. 2006. 20:2671–2681.
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