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1 REVIEW ARTICLE pissn /eISSN YUJM 2012;29(2): AMP-activated protein kinase 활성화기전과관련약물의효과 영남대학교의과대학약리학교실 Effects of AMP-activated Protein Kinase Activating Compounds and Its Mechanism Hyoung Chul Choi Department of Pharmacology, College of Medicine, Yeungnam University, Daegu, Korea AMP-activated protein kinase (AMPK) is an important cellular fuel sensor. Its activation requires phosphorylation at Thr-172, which resides in the activation loop of the α1 and α2 subunits. Several AMPK upstream kinases are capable of phosphorylating AMPK at Thr-172, including LKB1 and CaMKKβ (Ca 2+ /calmodulindependent protein kinase kinaseβ). AMPK has been implicated in the regulation of physiological signals, such as in the inhibition of cholesterol fatty acid, and protein synthesis, and enhancement of glucose uptake and blood flow. AMPK activation also exhibits several salutary effects on the vascular function and improves vascular abnormalities. AMPK is modulated by numerous hormones and cytokines that regulate the energy balance in the whole body. These hormone and cytokines include leptin, adiponectin, ghrelin, and even thyroid hormones. Moreover, AMPK is activated by several drugs and xenobiotics. Some of these are in being clinically used to treat type 2 diabetes (e.g., metformin and thiazolidinediones), hypertension (e.g., nifedipine and losartan), and impaired blood flow (e.g., aspirin, statins, and cilostazol). I reviewed the precise mechanisms of the AMPK activation pathway and AMPK-modulating drugs. Key Words: AMPK, LKB1, Metformin, Nifedipine, Aspirin 서 론 살아있는세포의대사과정은 ATP 와 ADP 를에너지원으로사용하고 AMP 를생성하게된다. AMP-activated protein kinase (AMPK) 는 serine/threonine kinase로서지질과포도당대사의조절인자로알려져있으며, 당뇨와비만에중요한조절작용을한다. 1 AMPK 는세포내에너지소모시증가되는 AMP 에의해활성화되어 ATP 사용을억제시키며, 이화작용 (catabolism) 을유도하여에너지항상성 (homeostasis) 을유지하는데핵심적인역할을한다. 2 Received: November 12, 2012, Accepted: December 11, 2012 교신저자 :, , 대구광역시남구현충로 170 영남대학교의과대학약리학교실 Tel: (053) , Fax: (053) hcchoi@med.yu.ac.kr AMPK 는 α, β, γ3개의소단위로구성된 heterotrimeric complex 로이루어져있으며각각소단위들은 α1, α2, β1, β2, γ1, γ2, γ3 아형으로분류되어 12개의조합이있는것으로알려져있다. 3 이중 α 소단위의 N-말단 (N-terminal) 에촉매부위 (catalytic site) 가있으며, 이중 172번 threonine (Thr- 172) 이인산화 (phosphorylation) 되는것이활성화되는것이며, AMPK 의다른활성화부위는알려져있지않다. 4 따라서 AMPK 활성화를측정하는많은실험은 Thr-172에대한인산화항체를이용한실험이주로이루어진다. AMPK 의생리작용은대부분 α 소단위의촉매부위에의해나타나기때문에 α 소단위의아형분포를파악하는것이중요하며, α1 소단위는인체의대부분세포에서발현되며, α2 소단위는주로간, 심근, 골격근, 평활근등에서발현된다. 5 α 소단위의 C-말단에는 β, γ소단위와결합하는부위가있다. β 소단위에는 glycogen 부착부위 (glycogen binding domain) 를가져 glycogen 구 YUJM VOLUME 29, NUMBER 2, DECEMBER

2 조변화를감지하는것으로보고가 6 있지만, 생리학적의의는아직알려지지않고있으며,γ소단위에는 2군데의 AMP/ ATP 결합부위를가지고있어세포내에너지준위를감지하는역할을한다. 7 지방대사측면에서 AMPK 활성화는지방산합성을유도하는효소인 FAS (fatty acid synthase) 와 ACC (acetyl CoA carboxylase) 를억제하며 8, 콜레스테롤생합성의제한효소 (rate- limiting enzyme) 인 HMG-CoA reductase 를억제하므로체내지질생성조절에영향을미친다. 9 포도당의생성과정에는 gluconeogenesis 를억제하는작용을 10 하며, 근육세포의 GLUT4 양을증가시켜근육으로포도당이동을증가시키는작용을한다. 11 따라서당뇨병환자에서 AMPK 활성화를유도하면다양한치료기전을가지게된다. 이러한대사조절이외에 AMPK 는암세포를포함한여러종류의세포에서증식을억제하는작용을가지는데, cyclindependent kinase 억제인자인 p21을유도하여세포분열을감소시키며, 12 최근세포증식에중요한작용을한다고알려진 mtor (mammalian target of rapamycin) 를억제하는작용을동시에가진다고보고되었다. 13 AMPK 는혈관내피세포의보호작용에대해서도중요한관점을가지며, AMPK-eNOS-NO 신호전달경로를통해그효과를가진다. 그리고 AMPK 활성화는혈관내피세포의대사학적인자와인슐린저항성개선을통해혈관기능의유지에도영향을미친다. 14 AMPK 는다양한생체변화를유도하는데 SIRT1 신호전달을통한항노화작용, 15 NF-κB 억제에의한항염증작용, 16 myosin light chain kinase 발현억제와인산화 myosin light chain 감소를통한혈관이완작용 17 등이있다. AMPK 는저혈당, 과격한운동, 저산소증및허혈등 AMP/ ATP 비율을증가시키는신호전달과세포내부의스트레스반응에의해활성화되며, 정상환경에서는일반적으로활성화되어있지않다. AMPK 가활성화된경우이화반응을유도하여 ATP 생성을증가시키며, ATP 소모를유도하는반응인 (e.g., 생합성, 세포성장, 세포증식 ) 을억제하기때문에생체의에너지센서의역할을담당하고있다. 이런에너지항상성유지는 AMPK 가매개하는다양한생체기능변화에대한근간을이루고있다. AMPK 활성화를유도할수있는물질은인체의에너지대사조절을비롯한여러작용의변동을유발하기때문에연구에의의를가지며, 저자는 AMPK 활성화과정과이에변동을유발한다고알려진약물에대해기술하고자한다. 본론 1. AMPK 활성화기전 1) LKB1 에의한활성화기전 AMPK 활성화과정에는세포내부에서증가된 AMP/ATP 비율을γ 소단위에서인식하여 AMPK 가활성화되는기전과 AMPK 상위인산화효소 (upstream kinase) 에의하여 AMPK 가활성화되는기전이있다. 세포의에너지소모에의해증가된 AMP 는 α 소단위 Thr-172에인산화를유도하거나구조적인변동을통해 AMPK 활성화작용을나타내지만, 이와다르게 α 소단위에존재하는 Thr-172를직접적으로인산화시키는효소인 AMPK 상위인산화효소 (upstream kinase) 몇종류가알려졌다. 증가된 AMP 를감지하여 AMPK 가활성화되는기전은운동등육체적활동에서나타나는일반적인생리반응의일종이며, 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) 는세포를이용한여러실험과생체실험에서 AMPK 활성화를유도하기위해주로사용되는약물로서 adenosine transporter에의해세포내로들어간후 adenosine kinase에의해 ZMP로전환된다. 18 ZMP 는 AMP와유사한작용을하여 AMPK 를활성화하지만, 그효과는 AMP 에비해미약하다. AICAR 는현재여러질환의대해서임상시험 2상과정에있으며, 최근 AMP 외에 ADP도 AMPK 활성화과정에밀접한관련이있다고알려지고있다. 19 AMPK α 소단위 Thr-172를인산화하기위한상위인산화효소의종류는 liver kinase B1 (LKB1), Ca 2+ /calmodulin- dependent protein kinase kinase β(camkkβ), TGFβ-activated kinase (TAK-1) 등이알려져있다 (Fig. 1). LKB1은 serine/threonine protein kinase이며, lkb1 유전자에서발현되어지는효소단백질이다. 20 LKB1은 STRAD 나 MO25 와같은보조단백질들과결합하고있으며, 이들단백질이 LKB1의활성을증가시킨다는보고가 21 있으며, LKB1 은 AMP 가γ소단위에부착하는것을강화시킨다는보고도있다. 22 LKB1은 Peutz-Jeghers 증후군에서처음알려졌으며, LKB1 돌연변이에의해유발된 Peutz-Jeghers 증후군의경우대장용종이나, 대장암이발생된다고보고되는등 AMPK 활성화작용이외다양한 LKB1 작용이알려지고있다. 23 또한자궁경부암세포주인 HeLa S3와폐암세포주인 A 등일부암세포에서는 LKB1이결여되어있다고보고되어 LKB1이 78 YUJM VOLUME 29, NUMBER 2, DECEMBER 2012

3 AMP-activated Protein Kinase 활성화기전과관련약물의효과 Fig. 1. Regulation of AMPK by phosphorylation and adenine nucleotides (Adapted figure from Hardie DG, Genes Dev 2011; 25: ). 종양억제효과를가지는것을알수있으며, LKB1 이결여된경우암발생위험성증가와관련이있을것으로알려졌다. 이런일련의연구는 AMPK 활성감소에의한당뇨병등대사질환과 LKB1-AMPK 활성감소에의한발암과정의연관성이밝히는데도움이될것이다. LKB1 은 AMPK 와유사한많은종류의효소를인산화시킬수있지만, 세포증식을조절할수있는효소는 AMPK 가유일하기때문에 LKB1의종양억제효과는 AMPK 를매개하여나타나는것으로생각된다. Statin 계약물, metformin 등다수의약물의경우 AMP-dependent AMPK kinase인 LKB1의 428번 serine 을인산화시켜 AMPK 활성화작용을나타낸다고알려졌지만, sirt1 은 LKB1 을탈아세틸화시켜활성화시킨다는보고도있었다. 25 2) CaMKKβ 및기타기전에의한활성화기전 몇몇종류의세포에서는 Ca 2+ 에의해활성화되는 CaMKKβ 가 AMPK 활성화역할을담당하는것으로알려지며, 이과정은세포내 AMP/ATP 비율의변화와관계없이나타난다고보고되었다. 26 CaMKKβ 에의한 AMPK 활성화과정은세포내 Ca 2+ 증가가에너지소비과정의출발점으로작용하는신경세포, 혈관내피세포, T 림프구에서중요한역할을한다. C2C12 근육세포에서 alpha-lipoic acid 에의한 AMPK 활성화와갑상선호르몬과 thrombin에의한 AMPK 활성화에 CaMKKβ 가관련이있다고알려졌다. TAK-1 (known as MAP3K7 or MEKK7) 은 cytokine 수용 체와연결된하위인산화효소 (downstream kinase) 로 MAP kinase (JNK) 와 NF-κB 신호전달의상위효소로작용을한다. 27 TAK-1은종양괴사인자 (tumor necrosis factor) 매개 apoptosis 과정에서 AMPK 활성화를유도하는것으로알려졌지만, 생리적인중요성은아직많은연구가이루어지지않았다. AMPK 는 leptin, adiponectin, ghrelin, cannabinoids, 갑상선호르몬등인체의에너지균형을조절하는많은종류의호르몬이나사이토카인에의해활성화될수있다고보고되고있다. 28 지방세포에서분비되어지방축척을유도하는 leptin 은근육세포의 AMP 를증가시켜 AMPK 를활성화한다고알려졌지만시상하부에서는 AMPK 를억제하는작용이보고되었다. 29 Adiponectin 은근육세포의 AMP 를증가시키며, 간에서 AMPK 활성화를통해포도당감소를나타낸다고보고되었지만 30 상세한기전은아직연구가더필요한실정이다. 2. AMPK 활성조절약물 1) 당뇨병치료제및 aspirin 2형당뇨병의치료약물중에서 AMPK 활성화를유도할수있는약물은 2가지가있다. Metformin 은골격근에서포도당섭취증가, gluconeogenesis 감소효과를통해혈중포도당을감소시키는약물로잘알려져있지만, 최근 AMPK 활성화작용이알려졌고, 이는 metformin의당뇨병치료작용의새로운기전으로대두된다. 31 Metformin 은다양한실험에서 AMPK 활성화물질로사용하는대표적인약제가되고있다. Peroxisome proliferator activated receptorγ(pparγ) 에작용하여지방조직과골격근에서포도당섭취와산화를촉진시키고간, 골격근에서 insulin 작용을증강시키는 rosiglitazone은 AMPK 활성화작용이 32 알려져당뇨병약물로서의중요성이부각이되었지만, 심장독성으로인해 2010년에퇴출된상황이다. 이 2가지약제들의 AMPK 활성화과정에서의차이점은 metformin 은 LKB1 활성화를통해 AMPK 활성화가유도되지만, rosiglitazone 은세포내 AMP/ATP 비율의변화를통해 AMPK 활성화가나타나는것으로알려진다. Aspirin 에의한 AMPK 활성화작용에관한최근연구결과가알려졌으며, 33 선천성고혈압쥐 (spontaneous hypertensive rat, SHR) 에서 AMPK 활성화작용이강하게나타내기때문에 SHR에서관찰되는혈관평활근세포의과다증식을억제할수있는것으로알려지고있다. 그러나 SHR의대조군인 wistar kyoto rat 에서는 aspirin 에의한 AMPK 활성화가미약 YUJM VOLUME 29, NUMBER 2, DECEMBER

4 하게관찰되어혈관평활근세포의증식조절기능이적었으며, 이는고혈압등혈관질환환경에따라선택적인조절이가능한것을나타낸다. 34 또한 aspirin 의항염증작용은고유의 COX 억제에의한기전외에 AMPK 에의한염증억제도고려할가치가있는것으로생각된다. 2) 순환기계약물 Statin 계약물인 simvastatin 은직접작용으로간세포의 HMG- CoA reductase 를억제하여콜레스테롤생합성과정을감소시키는약물이지만, 혈관내피세포에서 AMPK 활성화작용을나타내었으며, 이는콜레스테롤생합성과정에있어간접작용을나타내는기전이된다. 35 이보고는 statin 계약물이콜레스테롤생합성과정에있어이중작용 (dual action) 을한다는의미를내포하고있다. Statin계약물에의한 AMPK 활성화과정은 LKB1이없는 A549 세포에서는나타나지않기때문에 LKB1이 AMPK 활성화에중요한역할을하고있다고보고되고있다. 최근항고혈압약물중몇종류가 AMPK 활성화를유도한다고알려졌다. 이는각각항고혈압약물의고유한치료작용기전외에 AMPK 활성화에의한 myosin light chain kinase 발현억제와인산화 myosin light chain 감소에의한혈관이완효과도같이있음을생각해볼수있다. 칼슘통로봉쇄제인 nifedipine은고유의혈관이완작용이외에혈관평활근세포에서증식과활성산소종 (reactive oxygen species) 의생성을감소시키는데, 이는 nifedipine에의한 AMPK 활성화와관련이있다고보고되었다. 36 세포증식억제작용은세포주기의중단에의한것으로알려졌으며, 칼슘통로봉쇄제가보이는여러생리적효과중혈관평활근세포증식억제에대한새로운기전이될수있다. AT1 수용체봉쇄제 (AT1 receptor blocker) 작용을통해혈압강하효과를나타내는 losartan 도 AMPK 활성화를유도하는작용이있으며, 세포주기의진행을중단시켜혈관평활근세포의증식을억제한다고보고되었다. 37 항고혈압약물에의한 AMPK 활성화는고유의혈관이완효과이외에다수의고혈압환자에서동반되어있는지질대사이상에항고혈압약물이치료적개입이가능하다는근거를마련할수있다. Cilostazol 에의한 AMPK 활성화작용은혈관평활근세포의과다증식과활성산소종의생성을억제한다고보고되었으며, cilostazol 에의해발현된 heme oxygenase-1 (HO-1) 이 AMPK 활성화를유도한다고알려졌다. 이보고에서 HO-1 억제제인 SNPP IX과 HO-1 specific sirna 를처리한실험군 Table 1. Various drugs that activate AMPK Type of treatment Treatment Primary reference Biguanide drugs Metformin Zou, et al Thiazolidinediones Rosiglitazone Boyle, et al NSAIDs Aspirin Hawley, et al Sung, et al Statins Simvastatin Choi, et al Ca 2+ channel blockers Nifedipine Sung, et al AT1 receptor blockers Losartan Kim, et al Phosphodiesterase inhibitors Cilostazol Kim, et al 은 cilostazol 을투여하여도 AMPK 활성화가나타나지않음을확인하였다. 38 또한 cilostazol은 AMPK 활성화를통해 NFκB 억제를유도한다고알려져고유의 phosphodiesterase 3억제제로서의효과와 AMPK 활성화에의한효과가기대된다. 결 론 본론에서기술된약물들은고유의치료효과이외에 AMPK 활성화를유도하는기전을가지는예로서새로운치료적적응증을얻을수있게하거나, 기존의치료효과에대해알려지지않았던기전을제시할수있는근거를마련할수있다 (Table 1). 다양한생체기능의변동을유발하는 AMPK 활성화의생리적중요성은강조할수있으며, 그기전과활성화물질을연구하는것은큰의미를가진다. 이연구에서는 AMPK 활성화에의해유도되는다양한생리기능의변화와 AMPK 가활성화되는기전을밝히고, 최근 AMPK 활성화를유도한다고알려진약물과그작용에대해서고찰하고정리하여제시된약물을이용한여러질환의치료에도움을주고자하였다. 참고문헌 1. Hardie DG. Minireview: the AMP-activated protein kinase cascade: the key sensor of cellular energy status. Endocrinology 2003;144: Winder WW, Thomson DM. Cellular energy sensing and signaling by AMP-activated protein kinase. Cell Biochem Biophys 2007;47: Hardie DG, Scott JW, Pan DA, Hudson ER. Management of cellular energy by the AMP-activated protein kinase system. FEBS Lett 2003;546: Hawley SA, Davison M, Woods A, Davies SP, Beri RK, Carling D, et al. Characterization of the AMP-activated protein kinase kinase from rat liver and identification of threonine 172 as 80 YUJM VOLUME 29, NUMBER 2, DECEMBER 2012

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110 Choi HC 위 (glycogen binding domain) 를가져 glycogen 구조변화를감지하는것으로보고가 [5] 있지만생리학적의의는아직알려지지않고있으며, γ 소단위에는 2군데의 AMP/ATP 결합부위를가지고있어세포내에너지준위를감지하는역할을한다 [6].

110 Choi HC 위 (glycogen binding domain) 를가져 glycogen 구조변화를감지하는것으로보고가 [5] 있지만생리학적의의는아직알려지지않고있으며, γ 소단위에는 2군데의 AMP/ATP 결합부위를가지고있어세포내에너지준위를감지하는역할을한다 [6]. Endocrinol Metab 27(2):109-115, June 2012 REVIEW ARTICLE AMP-activated protein kinase 활성화물질과생체기능조절 최형철 영남대학교의과대학약리학교실, 노인성혈관질환연구센터 AMP-activated protein kinase Activating Agent and Its Implication Hyoung