Endocrinol Metab.  2012 Jun;27(2):109-115. 10.3803/EnM.2012.27.2.109.

AMP-activated protein kinase Activating Agent and Its Implication

• Choi HC

• KMID: 1497647
• DOI: http://doi.org/10.3803/EnM.2012.27.2.109

Abstract

AMP-activated protein kinase (AMPK) is an important cellular fuel sensor. Activation of AMPK requires phosphorylation at threonine (Thr)-172, which resides in the activation loop of the alpha1 and alpha2 subunits. Several AMPK upstream kinases are capable of phosphorylating AMPK at Thr-172, including LKB1 and CaMKKbeta. AMPK has been implicated in the regulation of physiological signals, such as inhibition of cholesterol, fatty acid, protein synthesis, and enhancement of glucose uptake and blood flow. AMPK activation also exhibits several salutary effects on vascular function and improves vascular abnormalities. AMPK is activated by numerous drugs and xenobiotics. Some of these are in clinical use for the treatment of type 2 diabetes (e.g., metformin and thiazolidinediones), hypertension (e.g., nifedipine and losartan), and impaired blood flow (e.g., aspirin, statins, and cilostazol). Plant-derived xenobiotics or nutraceuticals that were claimed to have health benefits in diabetes or cancer have been reported to activate AMPK. These include resveratrol from red wine, epigallocatechin gallate from green tea, capsaicin from peppers, berberine, which is a yellow dye of the genus berberis, genistein from soy bean, and ginsenoside from ginseng panax. AMPK is also modulated by numerous hormones and cytokines that regulate energy balance at the whole body level, including leptin, adiponectin, ghrelin, and even thyroid hormones. This work shows that the precise mechanisms of AMPK kinase and AMPK interaction.

Keyword

AMP-activated protein kinase; AMPK activating agent; LKB1

MeSH Terms

Adiponectin
AMP-Activated Protein Kinases
Aspirin
Berberine
Berberis
Calcium-Calmodulin-Dependent Protein Kinase Kinase
Capsaicin
Catechin
Cholesterol
Cytokines
Dietary Supplements
Genistein
Ghrelin
Glucose
Hypertension
Insurance Benefits
Leptin
Metformin
Nifedipine
Panax
Phosphorylation
Phosphotransferases
Protein Kinases
Soybeans
Stilbenes
Tea
Threonine
Thyroid Hormones
Wine
Xenobiotics
AMP-Activated Protein Kinases
Adiponectin
Aspirin
Berberine
Calcium-Calmodulin-Dependent Protein Kinase Kinase
Capsaicin
Catechin
Cholesterol
Cytokines
Genistein
Ghrelin
Glucose
Leptin
Metformin
Nifedipine
Phosphotransferases
Protein Kinases
Stilbenes
Tea
Threonine
Thyroid Hormones
Xenobiotics

Figure

• 

  Fig. 1 Key processes of energy metabolism regulated by AMP-activated protein kinase (AMPK) (Adapted from Hardie DG, et al. J Physiol 574(Pt 1):7-15, 2006) [9].

• 

  Fig. 2 Regulation of AMP-activated protein kinase (AMPK) by phosphorylation and adenine nucleotides (Adapted from Hardie DG. Genes Dev 25:1895-1908, 2011) [30].

Reference

1. Hardie DG. Mini review: the AMP-activated protein kinase cascade: the key sensor of cellular energy status. Endocrinology. 2003. 144:5179–5183.

2. Winder WW, Thomson DM. Cellular energy sensing and signaling by AMP-activated protein kinase. Cell Biochem Biophys. 2007. 47:332–347.

3. Hardie DG, Scott JW, Pan DA, Hudson ER. Management of cellular energy by the AMP-activated protein kinase system. FEBS Lett. 2003. 546:113–120.

4. Hawley SA, Davison M, Woods A, Davies SP, Beri RK, Carling D, Hardie DG. Characterization of the AMP-activated protein kinase kinase from rat liver, and identification of threonine-172 as the major site at which it phosphorylates and activates AMP-activated protein kinase. J Biol Chem. 1996. 271:27879–27887.

5. Hudson ER, Pan DA, James J, Lucocq JM, Hawley SA, Green KA, Baba O, Terashima T, Hardie DG. A novel domain in AMP-activated protein kinase causes glycogen storage bodies similar to those seen in hereditary cardiac arrhythmias. Curr Biol. 2003. 13:861–866.

6. Scott JW, Hawley SA, Green KA, Anis M, Stewart G, Scullion GA, Norman DG, Hardie DG. CBS domains form energy-sensing modules whose binding of adenosine ligands is disrupted by disease mutations. J Clin Invest. 2004. 113:274–284.

7. Stapleton D, Mitchelhill KI, Gao G, Widmer J, Michell BJ, Teh T, House CM, Fernandez CS, Cox T, Witters LA, Kemp BE. Mammalian AMP-activated protein kinase subfamily. J Biol Chem. 1996. 271:611–614.

8. Ouchi N, Shibata R, Walsh K. AMP-activated protein kinase signaling stimulates VEGF expression and angiogenesis in skeletal muscle. Circ Res. 2005. 96:838–846.

9. Hardie DG, Hawley SA, Scott JW. AMP-activated protein kinase-development of the energy sensor concept. J Physiol. 2006. 574(Pt 1):7–15.

10. Foretz M, Ancellin N, Andreelli F, Saintillan Y, Grondin P, Kahn A, Thorens B, Vaulont S, Viollet B. Short-term overexpression of a constitutively active form of AMP-activated protein kinase in the liver leads to mild hypoglycemia and fatty liver. Diabetes. 2005. 54:1331–1339.

11. Stoppani J, Hildebrandt AL, Sakamoto K, Cameron-Smith D, Goodyear LJ, Neufer PD. AMP-activated protein kinase activates transcription of the UCP3 and HKII genes in rat skeletal muscle. Am J Physiol Endocrinol Metab. 2002. 283:E1239–E1248.

12. Ferri N. AMP-activated protein kinase and the control of smooth muscle cell hyperproliferation in vascular disease. Vascul Pharmacol. 2012. 56:9–13.

13. Motoshima H, Goldstein BJ, Igata M, Araki E. AMPK and cell proliferation-AMPK as a therapeutic target for atherosclerosis and cancer. J Physiol. 2006. 574(Pt 1):63–71.

14. Cahoon WD Jr, Crouch MA. Preprocedural statin therapy in percutaneous coronary intervention. Ann Pharmacother. 2007. 41:1687–1693.

15. Choi HC, Song P, Xie Z, Wu Y, Xu J, Zhang M, Dong Y, Wang S, Lau K, Zou MH. Reactive nitrogen species is required for the activation of the AMP-activated protein kinase by statin in vivo. J Biol Chem. 2008. 283:20186–20197.

16. Han Y, Wang Q, Song P, Zhu Y, Zou MH. Redox regulation of the AMP-activated protein kinase. PLoS One. 2010. 5:e15420.

17. Wang Y, Liang Y, Vanhoutte PM. SIRT1 and AMPK in regulating mammalian senescence: a critical review and a working model. FEBS Lett. 2011. 585:986–994.

18. Salminen A, Hyttinen JM, Kaarniranta K. AMP-activated protein kinase inhibits NF-κB signaling and inflammation: impact on healthspan and lifespan. J Mol Med. 2011. 89:667–676.

19. Sung JY, Choi HC. Metformin-induced AMP-activated protein kinase activation regulates phenylephrine-mediated contraction of rat aorta. Biochem Biophys Res Commun. 2012. 421:599–604.

20. Gadalla AE, Pearson T, Currie AJ, Dale N, Hawley SA, Sheehan M, Hirst W, Michel AD, Randall A, Hardie DG, Frenguelli BG. AICA riboside both activates AMP-activated protein kinase and competes with adenosine for the nucleoside transporter in the CA1 region of the rat hippocampus. J Neurochem. 2004. 88:1272–1282.

21. Oakhill JS, Scott JW, Kemp BE. AMPK functions as an adenylate charge-regulated protein kinase. Trends Endocrinol Metab. 2012. 23:125–132.

22. Boudeau J, Sapkota G, Alessi DR. LKB1, a protein kinase regulating cell proliferation and polarity. FEBS Lett. 2003. 546:159–165.

23. Zeqiraj E, Filippi BM, Deak M, Alessi DR, van Aalten DM. Structure of the LKB1-STRAD-MO25 complex reveals an allosteric mechanism of kinase activation. Science. 2009. 326:1707–1711.

24. Sakamoto K, Göransson O, Hardie DG, Alessi DR. Activity of LKB1 and AMPK-related kinases in skeletal muscle: effects of contraction, phenformin, and AICAR. Am J Physiol Endocrinol Metab. 2004. 287:E310–E317.

25. Giardiello FM, Welsh SB, Hamilton SR, Offerhaus GJ, Gittelsohn AM, Booker SV, Krush AJ, Yardley JH, Luk GD. Incerased risk of cancer in the Peutz Jeghers Syndrome. N Engl J Med. 1987. 316:1511–1514.

26. Carretero J, Medina PP, Blanco R, Smit L, Tang M, Roncador G, Maestre L, Conde E, Lopez-Rios F, Clevers HC, Sanchez-Cespedes M. Dysfunctional AMPK activity, signalling through mTOR and survival in response to energetic stress in LKB1-deficient lung cancer. Oncogene. 2007. 26:1616–1625.

27. Lan F, Cacicedo JM, Ruderman N, Ido Y. SIRT1 modulation of the acetylation status, cytosolic localization, and activity of LKB1. Possible role in AMP-activated protein kinase activation. J Biol Chem. 2008. 283:27628–27635.

28. Shen QW, Zhu MJ, Tong J, Ren J, Du M. Ca²⁺/calmodulin-dependent protein kinase kinase is involved in AMP-activated protein kinase activation by alpha-lipoic acid in C2C12 myotubes. Am J Physiol Cell Physiol. 2007. 293:C1395–C1403.

29. Momcilovic M, Hong SP, Carlson M. Mammalian TAK1 activates Snf1 protein kinase in yeast and phosphorylates AMP-activated protein kinase in vitro. J Biol Chem. 2006. 281:25336–25343.

30. Hardie DG. AMP-activated protein kinase: an energy sensor that regulates all aspects of cell function. Genes Dev. 2011. 25:1895–1908.

31. Minokoshi Y, Kim YB, Peroni OD, Fryer LG, Muller C, Carling D, Kahn BB. Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase. Nature. 2002. 415:339–343.

32. Yamauchi T, Kamon J, Minokoshi Y, Ito Y, Waki H, Uchida S, Yamashita S, Noda M, Kita S, Ueki K, Eto K, Akanuma Y, Froguel P, Foufelle F, Ferre P, Carling D, Kimura S, Nagai R, Kahn BB, Kadowaki T. Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nat Med. 2002. 8:1288–1295.

33. Hardie DG. The AMP-activated protein kinase pathway-new players upstream and downstream. J Cell Sci. 2004. 117(Pt 23):5479–5487.

34. Zou MH, Kirkpatrick SS, Davis BJ, Nelson JS, Wiles WG 4th, Schlattner U, Neumann D, Brownlee M, Freeman MB, Goldman MH. Activation of the AMP-activated protein kinase by the anti-diabetic drug metformin in vivo. Role of mitochondrial reactive nitrogen species. J Biol Chem. 2004. 279:43940–43951.

35. Boyle JG, Logan PJ, Ewart MA, Reihill JA, Ritchie SA, Connell JM, Cleland SJ, Salt IP. Rosiglitazone stimulates nitric oxide synthesis in human aortic endothelial cells via AMP-activated protein kinase. J Biol Chem. 2008. 283:11210–11217.

36. Hawley SA, Fullerton MD, Ross FA, Schertzer JD, Chevtzoff C, Walker KJ, Peggie MW, Zibrova D, Green KA, Mustard KJ, Kemp BE, Sakamoto K, Steinberg GR, Hardie DG. The ancient drug salicylate directly activates AMP-activated protein kinase. Science. 2012. 336:918–922.

37. Sung JY, Choi HC. Aspirin-induced AMP-activated protein kinase activation regulates the proliferation of vascular smooth muscle cells from spontaneously hypertensive rats. Biochem Biophys Res Commun. 2011. 408:312–317.

38. Sun W, Lee TS, Zhu M, Gu C, Wang Y, Zhu Y, Shyy JY. Statins activate AMP-activated protein kinase in vitro and in vivo. Circulation. 2006. 114:2655–2662.

39. Horman S, Morel N, Vertommen D, Hussain N, Neumann D, Beauloye C, El Najjar N, Forcet C, Viollet B, Walsh MP, Hue L, Rider MH. AMP-activated protein kinase phosphorylates and desensitizes smooth muscle myosin light chain kinase. J Biol Chem. 2008. 283:18505–18512.

40. Sung JY, Choi HC. Nifedipine inhibits vascular smooth muscle cell proliferation and reactive oxygen species production through AMP-activated protein kinase signaling pathway. Vascul Pharmacol. 2012. 56:1–8.

41. Kim JE, Choi HC. Losartan inhibits vascular smooth muscle cell proliferation through activation of AMP-activated protein kinase. Korean J Physiol Pharmacol. 2010. 14:299–304.

42. Kim JE, Sung JY, Woo CH, Kang YJ, Lee KY, Kim HS, Kwun WH, Choi HC. Cilostazol inhibits vascular smooth muscle cell proliferation and reactive oxygen species production through activation of AMP-activated protein kinase induced by heme Oxygenase-1. Korean J Physiol Pharmacol. 2011. 15:203–210.

43. Zang M, Xu S, Maitland-Toolan KA, Zuccollo A, Hou X, Jiang B, Wierzbicki M, Verbeuren TJ, Cohen RA. Polyphenols stimulate AMP-activated protein kinase, lower lipids, and inhibit accelerated atherosclerosis in diabetic LDL receptor-deficient mice. Diabetes. 2006. 55:2180–2191.

44. Wang S, Song P, Zou MH. Inhibition of AMP-activated protein kinase α (AMPKα) by doxorubicin accentuates genotoxic stress and cell death in mouse embryonic fibroblasts and cardiomyocytes: role of p53 and SIRT1. J Biol Chem. 2012. 287:8001–8012.

45. Kim YM, Hwang JT, Kwak DW, Lee YK, Park OJ. Involvement of AMPK signaling cascade in capsaicin-induced apoptosis of HT-29 colon cancer cells. Ann N Y Acad Sci. 2007. 1095:496–503.

46. Kang JH, Tsuyoshi G, Le Ngoc H, Kim HM, Tu TH, Noh HJ, Kim CS, Choe SY, Kawada T, Yoo H, Yu R. Dietary capsaicin attenuates metabolic dysregulation in genetically obese diabetic mice. J Med Food. 2011. 14:310–315.

47. Elmarakby AA, Ibrahim AS, Faulkner J, Mozaffari MS, Liou GI, Abdelsayed R. Tyrosine kinase inhibitor, genistein, reduces renal inflammation and injury in streptozotocin-induced diabetic mice. Vascul Pharmacol. 2011. 55:149–156.

48. Gencel VB, Benjamin MM, Bahou SN, Khalil RA. Vascular effects of phytoestrogens and alternative menopausal hormone therapy in cardiovascular disease. Mini Rev Med Chem. 2012. 12:149–174.

49. Chen D, Pamu S, Cui Q, Chan TH, Dou QP. Novel epigallocatechin gallate (EGCG) analogs activate AMP-activated protein kinase pathway and target cancer stem cells. Bioorg Med Chem. 2012. 20:3031–3037.

50. Jeong HW, Hsu KC, Lee JW, Ham M, Huh JY, Shin HJ, Kim WS, Kim JB. Berberine suppresses proinflammatory responses through AMPK activation in macrophages. Am J Physiol Endocrinol Metab. 2009. 296:E955–E964.

51. Jung JH, Lee JO, Kim JH, Lee SK, You GY, Park SH, Park JM, Kim EK, Suh PG, An JK, Kim HS. Quercetin suppresses HeLa cell viability via AMPK-induced HSP70 and EGFR down-regulation. J Cell Physiol. 2010. 223:408–414.

52. Ahn J, Lee H, Kim S, Park J, Ha T. The anti-obesity effect of quercetin is mediated by the AMPK and MAPK signaling pathways. Biochem Biophys Res Commun. 2008. 373:545–549.

53. Yang JM, Hung CM, Fu CN, Lee JC, Huang CH, Yang MH, Lin CL, Kao JY, Way TD. Hispidulin sensitizes human ovarian cancer cells to TRAIL-induced apoptosis by AMPK activation leading to Mcl-1 block in translation. J Agric Food Chem. 2010. 58:10020–10026.

54. Lin YC, Hung CM, Tsai JC, Lee JC, Chen YL, Wei CW, Kao JY, Way TD. Hispidulin potently inhibits human glioblastoma multiforme cells through activation of AMP-activated protein kinase (AMPK). J Agric Food Chem. 2010. 58:9511–9517.

55. Lee YK, Lee WS, Hwang JT, Kwon DY, Surh YJ, Park OJ. Curcumin exerts antidifferentiation effect through AMPKalpha-PPAR-gamma in 3T3-L1 adipocytes and antiproliferatory effect through AMPKα-COX-2 in cancer cells. J Agric Food Chem. 2009. 57:305–310.

56. Kim SJ, Jung JY, Kim HW, Park T. Anti-obesity effects of Juniperus chinensis extract are associated with increased AMP-activated protein kinase expression and phosphorylation in the visceral adipose tissue of rats. Biol Pharm Bull. 2008. 31:1415–1421.

57. Quan HY, Yuan HD, Jung MS, Ko SK, Park YG, Chung SH. Ginsenoside Re lowers blood glucose and lipid levels via activation of AMP-activated protein kinase in HepG2 cells and high-fat diet fed mice. Int J Mol Med. 2012. 29:73–80.