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 Chul Choi Department of Pharmacology, Aging-associated Vascular Disease Research Center, Yeungnam University College of Medicine, Daegu, Korea 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 α1 and α2 subunits. Several AMPK upstream kinases are capable of phosphorylating AMPK at Thr-172, including LKB1 and CaMKKβ. 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. (Endocrinol Metab 27:109-115, 2012) Key Words: AMP-activated protein kinase, AMPK activating agent, LKB1 서론살아있는세포의대사과정은 ATP와 ADP를에너지원으로사용하고 AMP를생성하게된다. AMP-activated protein kinase (AMPK) 는 serine/threonine kinase로서지질과포도당대사의조절인자로알려져있으며당뇨와비만에중요한조절작용을한다 [1]. AMPK는세포내에너지소모시증가되는 AMP에의해활성화되어 ATP 사용을억제시키며, 이화작용 (catabolism) 을유도하여에너지항상성 (homeostasis) 을유지하는데핵심적인역할을한다 [2]. AMPK는 α, β, γ 3개의소단위로구성된 heterotrimeric complex 로이루어져있으며각각소단위들은 α1, α2, β1, β2, γ1, γ2, γ3 아형으로분류되어 12개의조합이있는것으로알려져있다 [3]. 이중 α 소단위의 N-말단 (N-terminal) 에촉매부위 (catalytic site) 가있으며이중 172번 threonine (Thr-172) 가인산화 (phosphorylation) 되는것이활성화되는것이며 AMPK의다른활성화부위는알려져있지않다 [4]. 따라서 AMPK 활성화를측정하는많은실험은 Thr-172 에대한인산화항체를이용한실험이주로이루어진다. α 소단위의 C-말단에는 β, γ 소단위와결합하는부위가있다. β 소단위에는 glycogen 부착부 Corresponding author: Hyoung Chul Choi Department of Pharmacology, Aging-associated Vascular Disease Research Center, Yeungnam University College of Medicine, 170 Hyeonchung-ro, Nam-gu, Daegu, Korea Tel: +82-53-620-4353, Fax: +82-53-656-7995, E-mail: hcchoi@med.yu.ac.kr This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea Government (MEST) (2012-0000288) (2012). Copyright 2012 Korean Endocrine Society This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
110 Choi HC 위 (glycogen binding domain) 를가져 glycogen 구조변화를감지하는것으로보고가 [5] 있지만생리학적의의는아직알려지지않고있으며, γ 소단위에는 2군데의 AMP/ATP 결합부위를가지고있어세포내에너지준위를감지하는역할을한다 [6]. AMPK의생리작용은대부분 α 소단위의촉매부위에의해나타나기때문에 α 소단위의아형분포를파악하는것이중요하며 α1 소단위는인체의대부분세포에서발현되며, α2 소단위는주로간, 심근, 골격근, 평활근등에서발현된다 [7]. 지방대사측면에서 AMPK 활성화는지방산합성을유도하는효소인 fatty acid synthase (FAS) 와 acetyl CoA carboxylase (ACC) 를억제하며 [8] 콜레스테롤생합성의제한효소 (rate-limiting enzyme) 인 HMG-CoA reductase를억제하므로체내지질생성조절에영향을미친다 [9]. 포도당의생성과정에는 gluconeogenesis 를억제하는작용을 [10] 하며, 근육세포의 GLUT4 양을증가시켜근육으로포도당이동을증가시키는작용을한다 [11]. 따라서당뇨병환자에서 AMPK 활성화를유도하면다양한치료기전을가지게된다. 이러한대사조절이외에 AMPK는암세포를포함한여러종류의세포에서증식을억제하는작용을가지는데 cyclin-dependent kinase 억제인자인 p21을유도하여세포분열을감소시키며 [12], 최근세포증식에중요한작용을한다고알려진 mammalian target of rapamycin (mtor) 를억제하는작용을동시에가진다고보고되었다 [13]. AMPK는정상환경에서는일반적으로활성화되어있지않지만, 저혈당, 과격한운동, 저산소증및허혈등 AMP/ATP 비율을증가시키는신호전달과세포내부의스트레스반응에의해활성화된다. AMPK가활성화된경우이화반응을유도하여 ATP 생성을증가시키며, ATP 소모를유도하는반응인생합성, 세포성장, 세포증식등을억제하기때문에생체의에너지센서의역할을담당하고있다. 이런에너지항상성유지는 AMPK가매개하는다양한생체기능변화에대한근간을이루고있다. AMPK의대사학적인작용은간, 골격근, 지방세포, 시상하부등에서는비교적잘알려지고있지만, 혈관을포함한몇가지조직에서는각조직에대한고유의작용변화에대해서만주로연구되고대사학적역할은아직많은부분이알려지지않고있다. 동맥경화증치료에주로사용되고있는 statin계약물은 HMG- CoA reductase를억제하여콜레스테롤생합성을조절한다고보고되어순환기및대사질환의치료에많이투여되고있으며 lovastatin, simvastatin 등고전적약물과최근사용빈도가높아진 atorvastatin, rosuvastatin 등이포함된다 [14]. Statin계약물의치료기전에 AMPK 활성화작용이있을경우직접적으로 HMG-CoA reductase를억제하는효과와 AMPK 활성화를통한간접적인 HMG-CoA reductase 억제효과를가져콜레스테롤생합성억제에대해이중작용 (dual effect) 을나타낼수있으며, 동맥경화증병변부위에서과도한혈관평활근세포증식을억제하는효과를가지게될것이다. AMPK의주 요한작용인체내대사조절효과와혈관평활근세포등세포증식을 억제하는기전은현재동맥경화증의치료와같은방향성을가진다. 따라서 AMPK 활성화를유도하는약물은동맥경화증의예방과치 료에널리적용할수있다 [15]. AMPK 는혈관내피세포의보호작용에대해서도중요한관점을 가지며 AMPK-eNOS-NO 신호전달경로를통해그효과를가진다. 그리고 AMPK 활성화는혈관내피세포의대사학적인자와인슐린 저항성개선을통해혈관기능의유지에도영향을미친다 [16]. AMPK 는대사조절작용이외에다양한생체변화를유도하는데 SIRT1 신호전달을통한항노화작용 [17], NF-κB 억제에의한항염증 작용 [18], myosin light chain kinase 발현억제와인산화 myosin light chain 감소를통한혈관이완작용 [19] 등이있다. 이상에서 AMPK 활성화의생리적중요성은강조할수있으며, 그 기전과활성화물질을찾는것은큰의미를가진다 (Fig. 1). 이연구 에서는 AMPK 활성화에의해유도되는다양한생리기능의변화와 AMPK 가활성화되는기전을밝히고, 최근 AMPK 활성화를유도한 다고알려진약물과자연계물질의종류와그작용에대해서알아 보고자하였다. AMPK 활성화기전과생리적인변화 AMPK 활성화과정에는세포내부에서증가된 AMP/ATP 비율을 γ 소단위에서인식하여 AMPK 가활성화되는기전과 AMPK 상위인 산화효소 (upstream kinase) 에의하여 AMPK 가활성화되는기전이 Gglucogen synthesis Protein synthesis Gluconeogenesis Glucose uptake AMPK Fatty acid/ cholesterol synthesis Glycolysis Fatty acid oxidation Mitochondrial biogenesis 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].
AMPK Activating Agent and Its Implication 111 있다. 세포의에너지소모에의해증가된 AMP 는 α 소단위 Thr-172 에 인산화를유도하거나구조적인변동을통해 AMPK 활성화작용을 나타내지만, 이와다르게 α 소단위에존재하는 Thr-172 를직접적으로 인산화시키는효소인 AMPK 상위인산화효소 (upstream kinase) 몇 종류가알려졌다. 증가된 AMP 를감지하여 AMPK 가활성화되는기전은운동등육 체적활동에서나타나는일반적인생리반응의일종이며, 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) 는세포를이용 한여러실험과생체실험에서 AMPK 활성화를유도하기위해주로 사용되는약물로서 adenosine transporter 에의해세포내로들어간 후 adenosine kinase 에의해 ZMP 로전환된다 [20]. ZMP 는 AMP 와 유사한작용을하여 AMPK 를활성화하지만그효과는 AMP 에비해 미약하다. AICAR 는현재여러질환의대해서임상시험 2 상과정에 있으며, 최근 AMP 외에 ADP 도 AMPK 활성화과정에밀접한관련 이있다고알려지고있다 [21]. AMPK α 소단위 Thr-172 를인산화하기위한상위인산화효소의 종류는 liver kinase B1 (LKB1), Ca 2+ /calmodulin-dependent protein kinase kinase β (CaMKKβ), TGFβ-activated kinase (TAK-1) 등이알 려져있다 (Fig. 2). LKB1 은 serine/threonine protein kinase 이며 lkb1 유전자에서발 현되는효소단백질이다 [22]. LKB1 은 STRAD 나 MO25 와같은보조 단백질들과결합하고있으며이들단백질이 LKB1 의활성을증가시 킨다는보고가 [23] 있으며 LKB1 은 AMP 가 γ 소단위에부착하는것 을강화시킨다는보고도있다 [24]. Ca 2+ CaMKKβ Cytokines TAK1? AMPK LKB1 PP? ATP AMP ADP AMP ADP AMP AMPK-P ATP ADP ATP 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]. LKB1은 Peutz-Jeghers 증후군에서처음알려졌으며 LKB1 돌연변이에의해유발된 Peutz-Jeghers 증후군의경우대장용종이나대장암이발생된다고보고되는등 AMPK 활성화작용이외다양한 LKB1 작용이알려지고있다 [25]. 또한자궁경부암세포주인 HeLa S3와폐암세포주인 A549 [26] 등일부암세포에서는 LKB1이결여되어있다고보고되어 LKB1이종양억제효과를가지는것을알수있으며, LKB1이결여된경우암발생위험성증가와관련이있을것으로알려졌다. 이런일련의연구는당뇨병등대사질환과발암과정의연관성이밝히는데도움이될것이다. LKB1은 AMPK와유사한많은종류의효소를인산화시킬수있지만세포증식을조절할수있는효소는 AMPK가유일하기때문에 LKB1의종양억제효과는 AMPK를매개하여나타나는것으로생각된다. Statin계약물, metformin 등다수의약물의경우 AMP-dependent AMPK kinase인 LKB1의 428번 serine을인산화시켜 AMPK 활성화작용을나타낸다고알려졌지만, LKB1은탈아세틸화반응에의해서도활성화된다는보고도있었다 [27]. 몇몇종류의세포에서는 Ca 2+ 에의해활성화되는 CaMKKβ가 AMPK 활성화역할을담당하는것으로알려지며이과정은세포내 AMP/ATP 비율의변화와관계없이나타난다고보고되었다 [28]. CaMKKβ에의한 AMPK 활성화과정은세포내 Ca 2+ 증가가에너지소비과정의출발점으로작용하는신경세포, 혈관내피세포, T 임파구에서중요한역할을한다. C2C12 근육세포에서 alpha-lipoic acid 에의한 AMPK 활성화와갑상선호르몬과 thrombin에의한 AMPK 활성화에 CaMKKβ가관련이있다고알려졌다. TAK-1 (known as MAP3K7 or MEKK7) 은 cytokine 수용체와연결된하위인산화효소 (downstream kinase) 로 MAP kinase (JNK) 와 NF-κB 신호전달의상위효소로작용을한다 [29]. TAK-1 은종양괴사인자 (tumor necrosis factor) 매개 apoptosis 과정에서 AMPK 활성화를유도하는것으로알려졌지만, 생리적인중요성은아직많은연구가이루어지지않았다. AMPK는 leptin, adiponectin, ghrelin, cannabinoids, 갑상선호르몬등인체의에너지균형을조절하는많은종류의호르몬이나사이토카인에의해활성화될수있다고보고되고있다 [30]. 지방세포에서분비되어지방축척을유도하는 leptin은근육세포의 AMP를증가시켜 AMPK를활성화한다고알려졌지만시상하부에서는 AMPK 를억제하는작용이보고되었다 [31]. Adiponectin은근육세포의 AMP를증가시키며간에서 AMPK 활성화를통해포도당감소를나타낸다고보고되었지만 [32] 상세한기전은아직연구가더필요한실정이다. AMPK 활성화에대한상위인산화효소는상기에제시된몇가지가있지만이들은세포의종류와활성화유발환경에따라각각다르게작용하기때문에 AMPK 활성화에공통적으로작용하는경우는없는것으로알려져있다.
112 Choi HC AMPK 활성화를유도하는약물과그작용과의관련성생체내에서 AMPK를활성화시키는조건으로는산화스트레스 (oxidative stress), 허혈 (ischemia), 근육운동 (exercise), 산화질소 (nitric oxide) 등이보고되었다 [33]. 현재까지알려진 AMPK 활성화약물에는당뇨병치료제몇종류와 statin계약물등이보고되어있으며, 최근수종의고혈압약제들에서 AMPK 활성화작용이보고되고있다. AMPK 활성화를유도하는것으로알려진치료약물의종류와 AMPK와관련된치료작용은다음과같다. 2형당뇨병의치료약물중에서 AMPK 활성화를유도할수있는약물은 2가지가있다. Metformin은골격근에서포도당섭취증가, gluconeogenesis 감소효과를통해혈중포도당을감소시키는약물로잘알려져있지만최근 AMPK 활성화작용이알려졌고이는 metformin의당뇨병치료작용의새로운기전으로대두된다 [34]. Metformin은다양한실험에서 AMPK 활성화물질로사용하는대표적인약제가되고있다. Peroxisome proliferator activated receptor γ (PPAR γ) 에작용하여지방조직과골격근에서포도당섭취와산화를촉진시키고간, 골격근에서 insulin 작용을증강시키는 rosiglitazone 은 AMPK 활성화작용이 [35] 알려져당뇨병약물로서의중요성이부각이되었지만심장독성으로인해 2010년에퇴출된상황이다. 이 2가지약제들의 AMPK 활성화과정에서의차이점은 metformin은 LKB1 활성화를통해 AMPK 활성화가유도되지만, rosiglitazone 은세포내 AMP/ATP 비율의변화를통해 AMPK 활성화가나타나는것으로알려졌다. Aspirin에의한 AMPK 활성화작용은최근연구결과가보고되고 [36] 있으며, 선천성고혈압쥐 (spontaneous hypertensive rat, SHR) 에서 AMPK 활성화작용이강하게나타내기때문에 SHR에서관찰되는혈관평활근세포의과다증식을억제할수있는것으로알려지고있다. 그러나 SHR의대조군인 wistar kyoto rat에서는 aspirin에의한 AMPK 활성화가미약하게관찰되어질환환경에따른선택적인조절이가능하다고보고되었다 [37]. 또한 aspirin의항염증작용은고유의 COX 억제에의한기전외에 AMPK에의한염증억제도고려할가치가있는것으로생각된다. Statin계약물인 simvastatin 과 atorvastatin 은직접작용으로간세포의 HMG-CoA reductase를억제하여콜레스테롤생합성과정을감소시키는약물이지만혈관내피세포에서 AMPK 활성화작용을나타내었으며, 이는콜레스테롤생합성과정에있어간접작용을나타내는기전이된다 [38]. 이보고는 statin계약물이콜레스테롤생합성과정에있어이중작용 (dual action) 을한다는의미를내포하고있다. Statin계약물에의한 AMPK 활성화과정은 LKB1이없는 A549 세포에서는나타나지않기때문에 LKB1이 AMPK 활성화에중요한역할을하고있다고보고되고있다. 최근항고혈압약물중몇종류가 AMPK 활성화를유도한다고알 려졌다. 이는각각항고혈압약물의고유한치료작용기전외에 AMPK 활성화에의한 myosin light chain kinase 발현억제와인산화 myosin light chain 감소에의한혈관이완효과도같이있음을생각해볼 수있다 [39]. 칼슘통로봉쇄제인 nifedipine 은고유의혈관이완작용이외에혈 관평활근세포에서증식과활성산소종 (reactive oxygen species) 의 생성을감소시키는데이는 nifedipine 에의한 AMPK 활성화와관련 이있다고보고되었다 [40]. 세포증식억제작용은세포주기의중단에 의한것으로알려졌으며, 칼슘통로봉쇄제가보이는여러생리적효 과중혈관평활근세포증식억제에대한새로운기전이될수있다. AT 1 수용체봉쇄제 (AT 1 receptor blocker) 작용을통해혈압강하 효과를나타내는 losartan 도 AMPK 활성화를유도하는작용이있으 며, 세포주기의진행을중단시켜혈관평활근세포의증식을억제한 다고보고되었다 [41]. 항고혈압약물에의한 AMPK 활성화는고유의 혈관이완효과이외에다수의고혈압환자에서동반되어있는지질 대사이상에항고혈압약물이치료적개입이가능하다는근거를마 련할수있다. Cilostazol 에의한 AMPK 활성화작용은혈관평활근세포의과다 증식과활성산소종의생성을억제한다고보고되었으며, cilostazol 에 의해발현된 heme oxygenase-1 (HO-1) 이 AMPK 활성화를유도한다 고알려졌다. 이보고에서 HO-1 억제제인 SNPP IX 과 HO-1 specific sirna 를처리한실험군은 cilostazol 을투여하여도 AMPK 활성화가 나타나지않음을확인하였다 [42]. 또한 cilostazol 은 AMPK 활성화를 Table 1. Various drugs and herbal medicines that activates AMP-activated protein kinase Type of treatment Treatment Primary reference Biguanide drugs Metformin Zou et al., 2004 [34] Thiazolidinediones Rosiglitazone Boyle et al., 2008 [35] NSAIDs Aspirin Sung et al., 2011 [37] Statins Simvastatin Atorvastatin Choi et al., 2008 [15] Sun et al., 2006 [38] Ca 2+ channel blockers Nifedipine Sung et al., 2012 [40] AT1 receptor blockers Losartan Kim et al., 2010 [41] Phosphodiesterase inhibitors Cilostazol Kim et al., 2011 [42] Red wine Resveratrol Zang et al., 2006 [43] Pepper Capsaicin Kim et al., 2007 [45] Soy bean Genistein Elmarakby et al., 2011 [47] Green tea EGCG Chen et al., 2012 [49] Genus berberis Berberine Jeong et al., 2009 [50] Onion Quercetin Jung et al., 2010 [51] Salvia plebeia Hispirudin Yang et al., 2010 [53] Curcuma longa Curcumin Lee et al., 2009 [55] Juniperus chinensis Extract Kim et al., 2008 [56] Ginseng Panax Gingsenoside Re Quan et al., 2012 [57] EGCG, epigallocatechin gallate; NSAIDs, nonsteroidal antiinflammatory drugs.
AMPK Activating Agent and Its Implication 113 통해 NF-κB 억제를유도한다고알려져고유의 phosphodiesterase 3 억제제로서의효과와 AMPK 활성화에의한효과가기대된다. 이상의약물들은고유의치료효과이외에 AMPK 활성화를유도하는기전을가지는예로서새로운치료적적응증을얻을수있게하거나, 기존의치료효과에대해알려지지않았던기전을제시할수있는근거를마련할수있다 (Table 1). AMPK 활성화를유도하는자연계물질과그작용과의관련성식품또는자연계유래물질로서 AMPK 활성화작용을유도할수있는물질은적포도주에포함된 resvereatrol, 고추에서유래된 capsaicin, 콩에서유래된 genistein, 녹차의주성분인 catechin, 매자나무 (Genus berberis) 에서유래된 berberine, 양파껍질의 quercetin, 곰보배추 (Salvia plebeia) 에서유래된 hispidulin 과그외카레의주요성분인 curcumin과감기, 류마치스관절염에민간요법으로사용되었던향나무 ( Juniperus chinensis) 수액, 인삼의주요성분인 ginsenoside 등이알려져있다. 그러나이들물질들의공통적인화학구조는알려져있지않으며 AMPK에직접결합하는과정을통해활성화를유도하지는않는다고생각된다. 제시된자연계물질몇종류는미토콘드리아 ATP 합성과정을억제하여 AMP/ATP 비율을증가시키는것으로알려져있으며, 이들자연계물질들은식물의 2차대사산물로대개곤충에대한방어작용의일환으로생성된것으로추측된다. Resveratrol은항산화작용, 혈중지질의개선, 항염증작용등이예전부터알려져있지만그기전이명확하지않았고최근 resveratrol 작용기전으로 AMPK 활성화작용이대두되고있다 [43]. Resveratrol 은간세포, 신경세포, 혈관내피세포등에서 AMPK 활성화작용이알려졌으며, 각각콜레스테롤생합성감소, 신경세포및혈관내피세포보호효과와관련이있다고알려졌다. Resveratrol에의한 AMPK 활성화기전은 NAD-의존성 deacetylase 단백인 sirt1에의해 LKB1이탈아세틸화되어매개된다고알려졌다 [44]. Capsaicin 은고추에서매운맛을나타내는물질로서 HT-29 대장암세포에서 AMPK 활성화하여 apoptosis를매개한다고보고되고 [45] 있으며, 비만쥐에서 capsaicin을식이로섭취한경우에도 AMPK 활성화를통하여대사조절작용이나타난다고보고되었다 [46]. Genistein은콩에서추출된단백질로서항산화작용, tyrosine kinase 억제작용을통하여다양한생체작용을유발하는것으로알려지고있지만, 최근 AMPK 활성화작용이보고되어그중요성이증가하고있다 [47]. 상기 genistein 의효과들중일부는 AMPK 활성화를경유하여나타난다고알려져있으며, genistein은여성호르몬수용체인 ERα에작용할수있는것으로알려져여성에게서심혈관질환이적은이유를 ERα-AMPK 측면에서생각해볼수있게한다 [48]. Catechin의한종류인 epigallocatechin gallate (EGCG) 는녹차에 서유래되는 polyphenol 로서다양한생리작용이알려졌다. 항산화작용과활성산소제거기능은비타민 C와비타민 E에비교해강한활성산소제거효과를가지고있으며, 항산화작용으로인하여심혈관계보호효과가있다. EGCG는유방암세포주에서 AMPK 활성화를유도하여세포증식을감소시켰다. 이작용은 AMPK 하위단계로 p21 발현을증가시키고, mtor을억제하여증식을감소시킨다는보고가있었다 [49]. Berberine은매자나무 (Genus berberis) 나황련 (Coptis japonica) 에서추출된물질로서대식세포에서염증을억제한다고알려졌으며이작용은 AMPK 활성화에의한항염증작용이라고보고되었다 [50]. 이보고에서 berberine은세균내독소 (lipopolysaccharide) 가유도하는 IL-1β, IL-6, inos, MCP-1, COX-2 및 matrix metalloprotease-9 발현을억제하였다. Quercetin 은양파의껍질에서주로함유되어있는물질로서 AMPK 활성화작용을유도한다고알려졌다. 이는 quercetin 이암세포주인 HeLa 세포에서 AMPK 활성화작용을통하여상피세포성장인자수용체 (epidermal growth factor receptor) 를억제하여증식을감소시키는것과관련이있다 [51]. 또한 quercetin 이비만억제효과를나타내는것이 AMPK 활성화와관련이있다고보고되었다 [52]. Hispidulin은곰보배추 (Salvia plebeia) 의어린잎에포함된 flavonoid 성분으로서 AMPK 활성화를유도한다고보고되었다. Hispidulin에의한 AMPK 활성화는난소암에서 apoptosis 를일으키며 [53], glioblastoma multiforme 뇌종양세포에서는 mtor 억제와함께 p21을유도하여암세포증식을감소시킨다는보고가있다 [54]. Curcumin은카레특유의노란색에포함된성분으로강황 (Curcuma longa) 의뿌리에서유래된다. 항산화작용과항염증작용을가지며, 암세포의증식을억제한다고알려져있다. 최근 curcumin의대사학적효과는 gluconeogenesis 감소와근육의포도당섭취를증가시키는작용을통하여나타난다고보고되었으며이러한작용은 curcumin이 AMPK 활성화를유도하기때문이라고알려졌다 [55]. 향나무 (Juniperus chinensis) 의고온추출액은고지방식이를한쥐의내장지방조직에서 AMPK 발현과활성도증가를유도하여비만억제작용을나타낸다고보고되었다 [56]. 인삼은다양한생리작용이있다고알려지며, 인삼에서분리된 ginsenoside Re 분획은간세포에서 AMPK를활성화하여혈중포도당과지질대사를개선한다는보고가있었다 [57]. 이상에서제시된자연계물질도천연물약물로개발될경우 AMPK 활성화에의한치료효과를얻을수있을것으로사료되기때문에더욱연구가필요하며, 이는 AMPK의다양한작용을가지지만천연물의특성으로부작용이적은약물이될수있을것이다 (Table 1).
114 Choi HC 참고문헌 1. Hardie DG: Mini review: the AMP-activated protein kinase cascade: the key sensor of cellular energy status. Endocrinol 144:5179-5183, 2003 2. Winder WW, Thomson DM: Cellular energy sensing and signaling by AMP-activated protein kinase. Cell Biochem Biophys 47:332-347, 2007 3. Hardie DG, Scott JW, Pan DA, Hudson ER: Management of cellular energy by the AMP-activated protein kinase system. FEBS Lett 546:113-120, 2003 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 271: 27879-27887, 1996 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 13:861-866, 2003 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 113:274-284, 2004 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 271:611-614, 1996 8. Ouchi N, Shibata R, Walsh K: AMP-activated protein kinase signaling stimulates VEGF expression and angiogenesis in skeletal muscle. Circ Res 96:838-846, 2005 9. Hardie DG, Hawley SA, Scott JW: AMP-activated protein kinase-development of the energy sensor concept. J Physiol 574(Pt 1):7-15, 2006 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 54:1331-1339, 2005 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 283:E1239-E1248, 2002 12. Ferri N: AMP-activated protein kinase and the control of smooth muscle cell hyperproliferation in vascular disease. Vascul Pharmacol 56:9-13, 2012 13. Motoshima H, Goldstein BJ, Igata M, Araki E: AMPK and cell proliferation-ampk as a therapeutic target for atherosclerosis and cancer. J Physiol 574(Pt 1):63-71, 2006 14. Cahoon WD Jr, Crouch MA: Preprocedural statin therapy in percutaneous coronary intervention. Ann Pharmacother 41:1687-1693, 2007 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 283:20186-20197, 2008 16. Han Y, Wang Q, Song P, Zhu Y, Zou MH: Redox regulation of the AMPactivated protein kinase. PLoS One 5:e15420, 2010 17. Wang Y, Liang Y, Vanhoutte PM: SIRT1 and AMPK in regulating mammalian senescence: a critical review and a working model. FEBS Lett 585: 986-994, 2011 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 89:667-676, 2011 19. Sung JY, Choi HC: Metformin-induced AMP-activated protein kinase activation regulates phenylephrine-mediated contraction of rat aorta. Biochem Biophys Res Commun 421:599-604, 2012 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. 88:1272-1282, 2004 21. Oakhill JS, Scott JW, Kemp BE: AMPK functions as an adenylate chargeregulated protein kinase. Trends Endocrinol Metab 23:125-132, 2012 22. Boudeau J, Sapkota G, Alessi DR: LKB1, a protein kinase regulating cell proliferation and polarity. FEBS Lett 546:159-165, 2003 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 326:1707-1711, 2009 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 287:E310-E317, 2004 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 316:1511-1514, 1987 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 26:1616-1625, 2007 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 283:27628-27635, 2008 28. Shen QW, Zhu MJ, Tong J, Ren J, Du M: Ca 2+ /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 293:C1395-C1403, 2007 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 281:25336-25343, 2006 30. Hardie DG: AMP-activated protein kinase: an energy sensor that regulates all aspects of cell function. Genes Dev 25:1895-1908, 2011 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 415:339-343, 2002 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 8:1288-1295, 2002 33. Hardie DG: The AMP-activated protein kinase pathway-new players upstream and downstream. J Cell Sci 117(Pt 23):5479-5487, 2004 34. Zou MH, Kirkpatrick SS, Davis BJ, Nelson JS, Wiles WG 4th, Schlattner
AMPK Activating Agent and Its Implication 115 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 279: 43940-43951, 2004 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 283:11210-11217, 2008 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 336:918-922, 2012 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 408:312-317, 2011 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. Circ 114:2655-2662, 2006 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 283:18505-18512, 2008 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 56:1-8, 2012 41. Kim JE, Choi HC: Losartan inhibits vascular smooth muscle cell proliferation through activation of AMP-activated protein kinase. Korean J Physiol Pharmacol 14:299-304, 2010 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 15:203-210, 2011 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 55:2180-2191, 2006 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 287:8001-8012, 2012 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 1095:496-503, 2007 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 14:310-315, 2011 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 55:149-156, 2011 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 12:149-174, 2012 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 20:3031-3037, 2012 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 296:E955-E964, 2009 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 223: 408-414, 2010 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 373:545-549, 2008 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 TRAILinduced apoptosis by AMPK activation leading to Mcl-1 block in translation. J Agric Food Chem 58:10020-10026, 2010 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 58:9511-9517, 2010 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. 57:305-310, 2009 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 31:1415-1421, 2008 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 29:73-80, 2012