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1 대한내분비학회지 : 제 25 권제 1 호 /jkes 지상강좌 생체에너지대사조절에서 AMPK 의역할 경희대학교의과대학생화학분자생물학교실 하주헌 이수호 Role of AMPK in the Regulation of Cellular Energy Metabolism Joohun Ha, Sooho Lee Department of Biochemistry and Molecular Biology, College of Medicine, Kyung Hee University 서론현대사회에서는비만, 당뇨병, 고지혈증및심혈관계질환등으로나타나는복합적원인으로대사장애가급격히증가하고있다. 그중에서도특히에너지항상성의불균형은근육, 간, 그리고지방세포의기능이상을초래하고, 그로인해대사성질환이발생된다 [1]. 에너지대사조절의이상은인슐린저항성에기인하며, 이는대사장애의다양한병리생리학적인요인으로작용할것으로생각되지만, 이에대한자세한조절메커니즘은밝혀져있지않은상황이다 [2]. 최근연구결과들은 AMPK (AMP-activated protein kinase) 를중심으로생체내의에너지인식및항상성조절이이루어지며, 당과지방의대사에있어서중요한역할을한다는사실을밝히고있으며, 이러한에너지센서의이상은대사성질환을비롯한심혈관계질환, 암발생과도연관성이높은 것으로나타나고있다 [3]. 세포내의에너지항상성유지에센서역할을하는효소인 AMPK는대사성스트레스나운동에의해세포내의에너지가감소하는경우, 즉 ATP가고갈되어 AMP/ATP 비율이증가하는경우에서활성화되어 ATP를소비하는과정 ( 예를들어, 지방산합성과콜레스테롤합성 ) 을억제하고 ATP 를생산하는과정 ( 예를들어, 지방산산화와해당과정 ) 을촉진한다 [4](Fig. 1). AMPK의활성화에대한효과는에너지대사조절과밀접하게연관되어있는표적장기 ( 간, 근육, 지방, 췌장 ) 에관여되어있다 [5]. 간에서 AMPK가활성화가되면지방산과콜레스테롤의합성을억제하고지방산의산화를촉진한다. 골격근에서 AMPK가활성화되면지방산의산화와당흡수를촉진하며지방세포에서는지방분해와지방생성을억제한다. 또한췌장 β세포에서 AMPK의활성화는인슐린분비를촉진시킨다. 이러한 AMPK의역할과관 Fig. 1. Regulation of energy homeostasis of the AMPK system. Figure from Hardie DG, 2007[4]

대한내분비학회지 : 제 25 권제 1 호 2010 련하여대사성질환의약물타겟으로많은연구가이루어져왔다. 이러한관점에서볼때, AMPK는대사성질환의발생에있어중추적인역할을담당하고있을가능성을의미한다 [6]. 본강좌에서는지금까지의여러연구결과들을바탕으로전반적인대사작용의조절에대한 AMPK의역할에대해살펴보고자한다. 1. AMPK의구조 AMPK는 serine/threonine kinase의일원으로하나의 catalytic α subunit (α1 또는 α2) 과두개의 regulatory subunit β (β1 또는 β2) 와 γ (γ1, γ2 또는 γ3) 로 heterotrimeric complex를이루고있다 [3,7](Fig.

2 대한내분비학회지 : 제 25 권제 1 호 2010 련하여대사성질환의약물타겟으로많은연구가이루어져왔다. 이러한관점에서볼때, AMPK는대사성질환의발생에있어중추적인역할을담당하고있을가능성을의미한다 [6]. 본강좌에서는지금까지의여러연구결과들을바탕으로전반적인대사작용의조절에대한 AMPK의역할에대해살펴보고자한다. 1. AMPK의구조 AMPK는 serine/threonine kinase의일원으로하나의 catalytic α subunit (α1 또는 α2) 과두개의 regulatory subunit β (β1 또는 β2) 와 γ (γ1, γ2 또는 γ3) 로 heterotrimeric complex를이루고있다 [3,7](Fig. 2). 각 subunit의조직내분포와발현정도의차이는다음과같다. Catalytic α1 subunit은신장, 폐와지방조직에많이분포되어있는반면에 catalytic α2 subunit은주로심장, 근육과간에분포되어있다. Regulatory β1 subunit은주로간에분포되어있으며 β2 subunit의경우에는근육에분포되어있다. Regulatory γ1과 γ2 subunits는조직내광범위하게분포하고있지만, γ3는근육에서특이적으로높게분포하고있는것으로보인다. α subunit의 N-terminal 부분에는 catalytic domain을포함하고있으며, 이 domain에는 upstream kinases에의한 AMPK의인산화및활성화중요한역할을하는 threonine residue Thr172가존재한다 [8,9]. α subunit의 C-terminal 부 분에는 β와 γ subunits과의결합에필요한자리가포함되어있다 [10]. β subunit의 C-terminal 부분은 functional αβγ complex를형성하는데중요한역할을하며, β subunit의중심부분에는그기능이확실하게밝혀지지않은 glycogen -binding domain (GBD) 이포함되어있다 [11,12]. γ subunit 은다양한 N-terminal regions과 AMP 또는 ATP 결합에필요한 4개의 cystathionine-β synthase (CBS) domains로이루어져있다 [13]. AMPK의 heterotrimeric complex를구성하는 3개의다른 subunits의다양한조합과조직특이적발현으로 AMPK에의한특정대사과정제어가이루어질수있을것으로여겨진다. 2. AMPK의조절 AMPK의활성화조절은 AMP에의한 allosteric activation 과 upstream kinases에의해 AMPK의 catalytic subunit에위치한 threonine residue Thr172의인산화과정이포함된다 (Fig. 3). 두기전의연합효과는 1,000배이상의 kinase 활성화를가능하게함으로써세포내에너지상태의작은변화에도매우민감하게반응한다 [14]. AMP에의한활성화작용은 ATP와길항작용을이루고있기때문에 AMPK의활성화는오직 AMP 변화에의해서만결정되는것이아니라 AMP/ATP ratio에의해결정된다 [15]. 또한 AMPK의활성화를증가시키는또다른기전으로 adenylate kinase가존재 Fig. 2. Subunit structures of AMPK. Figure from Towler et al., 2007[3]

3 - 하주헌외 1 인 : 생체에너지대사조절에서 AMPK 의역할 - Fig. 3. Regulation of AMPK activation. Figure from Viollet et al., 2009[58]. 할수있기때문에 AMP와 ATP는세포내에서상호보완적으로다양한작용을한다 [16]. AMPK의 regulatory γ subunit에 AMP의결합으로 allosteric activation이촉진되고, upstream kinases에의해 threonine residue Thr172에인산화가이루어지며, 이는 protein phosphatases (PP-2C) 에의한탈인산화과정을억제시킨다 [17,18]. LKB1[19,20] 과 Ca 2+ /calmodulin-dependent kinase kinase β (CaMKK β)[21,22] 는 AMPK의 upstream kinases로작용한다. 종양억제인자로알려진 LKB1은두개의 accessory subunits (STRAD와 MO25) 와복합체를이루고있다. 이복합체는 AMP-dependent pathway를통해지속적인활성을나타내며 AMPK의활성화를촉진시킨다. 최근연구에따르면, 간에서는 LKB1의아세틸화가 LKB1의세포내위치와활성에관여하는것으로나타났다 [23]. In vivo 실험에서 starved-refed rats와비교해 48 hr starved rats의간에서 LKB1의아세틸화가 60% 정도감소되었고, 이와같은변화는 LKB1과 AMPK의활성증가와관련이있는것으로보고되었다. 이로써 NAD(+) 의존적탈아세틸화효소인 SIRT1의작용에의한 LKB1의탈아세틸화와 LKB1에의한 AMPK의활성화기전사이의연관가능성을보여주고있다 [23]. AMP level의변화와상관없이 AMPK의활성화와관련된또다른경로로서세포질내의 Ca 2+ level의변화에반응하는 CaMKKβ가있다. 3. AMPK의역할 1) 당대사항상성에서 AMPK의역할당대사항상성은간에서의당생성과말초조직 ( 근육, 지방등 ) 에서의당흡수사이의균형을통하여유지하게된다. 당뇨병환자에서의간혈당증가는공복시고혈당을일으키는주요원인이된다 [2]. AICAR 또는 metformin과같은 AMPK의활성화약물들이간에서당생산을억제시키는것으로보고됨으로써간에서의당생성조절에 AMPK의역할이중요하다는것을입증하였다 [24,25]. 최근연구에따르면, metformin의혈당감소효과를조절하는기전으로 LKB1/ AMPK의활성화조절을이용하는것이밝혀졌다 [26]. 또한, AMPKα2 catalytic subunit의 constitutively active form (AMPKα2-CA) 을이용한생쥐실험을통하여간내의당생성억제를통해정상마우스뿐만아니라당뇨병모델의마우스에서도혈당저하가나타남이증명되었다 [27]. AICAR 를처리하거나 AMPK-CA를발현하는간세포에서 gluconeogenesis에관여하는 PEPCK (phosphoenolpyruvate carboxykinase) 또는 G6Pase (glucose-6-phosphatase) 등의유전자발현이감소되고, 이에따라당생성억제를일으킨다고보고되었다 [27,28]. AMPK에의한당생성억제기전으로 CREB의활성을조절하는 coactivator인 TORC2 (transducer of regulated CREB activity 2) 의인산화조절을이용하는것이밝혀졌다 [29]. TORC2는 CREB를통한직접적 PGC-1α 전사발현조절을매개하고 gluconeogenic targets인 PEPCK와 G6Pase의전사조절도매개하는것으로보고되었다. TORC2는세포내에너지상태의변화에반응하여움직이는다양한신호전달경로에의해조절된다 (Fig. 4). 당대사항상성유지에있어서간내의 AMPK 활성화와지방세포에서분비되는각종호르몬사이의생리적연관성이있는것으로나타났다. Adipokine의일종인 resistin이결핍된마우스에서간내의당생성억제와혈당량감소는부분적으로간에서의 AMPK의활성화와 gluconeogenic enzymes의발현량감소와관련되어있는것으로보고되었다 [30]. Adiponectin의주입은혈당량과 gluconeogenic enzymes의발현량모두감소시키는것으로보고되었다. 이와같은변화는 AMPK가간에서의당대사에중요한역할

4 대한내분비학회지 : 제 25 권제 1 호 2010 Fig. 4. AMPK and the regulation of hepatic metabolism. Figure from Viollet et al., 2009[58]. Fig. 5. AMPK and the regulation of skeletal muscle metabolism. Figure from Viollet et al., 2009[58]. 을수행함을보여준다 [31]. 근육은생체내의당흡수를담당하는기관이다. 인슐린은세포표면으로당수송체인 GLUT4의이동을촉진시켜근육내로당유입을증가시킨다 (Fig. 5). 운동에의한근수축이나 AICAR와같은약물에의한 AMPK 활성화는근육의당유입을촉진시키며인슐린에의한당흡수증가기전과는다른것으로보인다. 정상군과당뇨군에서 AICAR의 처리는근육내 GLUT4의양을증가시키고이러한기전으로당유입을효과적으로증가시킨다 [32]. 근육내 AMPK 의활성화는제2형당뇨병환자에서보이는인슐린신호전달의저하를개선시킴으로써당유입을촉진시킬가능성이있다. AMPK를활성화시키는많은상위신호들이비교적잘알려져있지만 [15], 근육의당수송에관여하는 AMPK 의하위신호전달기전은불분명한상태이다. Akt의하위

5 - 하주헌외 1 인 : 생체에너지대사조절에서 AMPK 의역할 - 표적인 160kDa의 Akt 기질 (AS160/TBC1D4) 은인슐린자극에의한당유입을조절하는데중요한역할을하는것으로최근에보고되었다. 근육의당수송조절을매개하는 AMPK의또다른하위표적으로 TBC1D1이연관될가능성이있다 [33]. 운동이나 AICAR에의한 AMPK의활성화는인슐린과유사하게근육에서 AS160/TBC1D4 인산화됨을확인하였다 [34]. 이러한결과를통해, AMPK의활성에따른당유입의증가는 AS160/TBC1D4에의해매개됨을알수있다. 일부사이토카인은 AMPK의활성화를통해근육에서의당수송촉진을매개한다. Adipokine의일종인 leptin이말초조직에서당유입을증가시키는것으로최근에보고되었다 [35,36]. Leptin이선택적으로근육내 AMPKα2의인산화및활성화를촉진시키는것으로밝혀짐으로써, leptin에의해매개되는당수송촉진이 AMPK에의해조절됨이확인되었다 [37]. 또한 adiponectin도정상군과비만군의근육에서당수송을증가시키는것으로보고되었다 [38]. 이러한결과들을종합해볼때근육에서의 AMPK는당수송을조절함으로써당대사항상성에중요한역할을담당할것으로보인다. 따라서, AMPK는당대사조절과정에필수적인매개인자이며, AMPK의신호전달경로는대사질환치료에중요한표적이된다. 2) 지방대사조절에서 AMPK의역할 AMPK는지방산의합성과분해를매개함으로써간지방대사의조절에중요한역할을담당한다 (Fig. 4). AMPK의활성화는 ATP를소비하는과정 ( 예를들어, 지방산합성과콜레스테롤합성 ) 에필요한효소인 acetyl-coa carboxylase (ACC) 와 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase) 를인산화및불활성화시킨다. AMPK 는 fatty acid synthase, pyruvate kinase 그리고 ACC와같은지질합성에관계된유전자발현을억제시킨다 [39,40]. Malonyl-CoA 를합성하는 ACC 효소는지방산합성에중요한전구체이며미토콘드리아의지방산산화에대한잠재적인억제자로작용한다. AMPK에의한 ACC 불활성화는 malonyl-coa 의농도저하를초래하고 carnitine palmitoyltransferase-1 (CPT-1) 의활성도를증가시켜지방산산화를증가시킨다 [41]. 정상군과비만군에서의 AICAR 또는 metformin 처리, 간에서의 AMPKα2-CA 과발현은지질산화의증가지표인 β-hydroxybutyrate level을증가시키고혈중중성지방수치를감소시킨다 [24,25,27]. 그러나간특이적 AMPKα2 제거는혈중중성지방수치를증가시키고간에서의지질합성을증가시키는것으로보고되었다 [42]. 이는 AMPK가지방합성의감소와지방분해의증가를통해간지방대사의균형을이루고있음을보여준다. 또한, AMPK는근육에서의지방산산화조절에중요한역할을하는것으로알려져있다 (Fig. 5). 설치류의골격근에서, AICAR 처리에의한 AMPK의활성화는 palmitate 산화를증가시킨다 [43]. 에너지항상성에핵심적인역할을하는 adipokine의일종인 leptin은 AMPK를활성화시킴으로써근육에서의지방산산화를증가시키는것으로보고되었다 [37]. 근육내 AMPK의활성화는 PGC-1α 발현을통해미토콘드리아관련유전자들의발현을증가시키는것으로보고되었다 [44]. AMPK가세포내 NAD(+) 의함량을증가시키고이를통해 NAD(+) 의존적탈아세틸화효소인 SIRT1이작용함으로써 PGC-1α의탈아세틸화및활성화가이루어지는것으로보고되었다 [45]. 비만군과제2형당뇨군에서비롯되는인슐린저항성과대사의경직성은근육내미토콘드리아의기능장애와관련이있는것으로보고되었다 [46]. 이는 AMPK에의한미토콘드리아의기능향상이인슐린저항성과대사의경직성을극복시켜줄수있음을보여주고있다. 3) 췌장 β-세포에서 AMPK의역할제2형당뇨병의병인은두가지원인, 즉인슐린분비장애와인슐린저항성의복합장애라고알려져있다 [47]. 만성적인고혈당상태는췌장 β-세포의대사에해로운영향을미치며세포내지질독성을유발하는데관여하는 fatty acyl-coa 함량을증가시키는것으로보고되었다 [48]. 이는췌장 β-세포에서의당자극에의한인슐린분비저하와세포자연사를일으키게된다. 최근연구에따르면, AMPK에의해조절되는신호전달체계는췌장 β-세포에서의당지질독성과제2형당뇨병의병인에있어중요한역할을할것이라고보고하였다. 췌장 β-세포에 metformin, TZDs 및 AICAR 처리는지방산의 β-산화를증가시키고당지질독성에의해유발된인슐린분비장애를막는다 [49,50]. AICAR 농도에의존적으로췌장 β-세포의기능을개선시키며만성적인고혈당상태에의해유발되는세포자연사를감소시킬수있는것으로보고되었다. 하지만, 췌장 β-세포사멸조절기전에있어 AMPK의역할은아직완전히규명되지않은상태이다 [51,52]. 췌장 β-세포에서생리적농도범위이상으로당농도를증가시켰을경우 AMPK의활성이급격하게감소하는것으로보고되었다 [53,54]. 이는 AMPK가세포내에너지상태의센서로작용하여인슐린분비조절에중요한역할을하고있음을나타낸다. 췌장 β-세포주나설치류및인간의췌장소도에 AICAR, metformin, TZDs, 그리고 berberine을처리하거나 AMPKα1-CA 과발현으로유도된 AMPK의활성화는당자극에의한인슐린분비를감소시키는것으로보고되었다 [55~57]. 반면에, AMPK의 dominant-negative form을과발현시켰을경우낮은당농도에서인슐린분비를촉진시킨다고보고되었다 [53,54]. 이러한결과들은 AMPK 의활성화가당대사의항상성유지를위해인슐린분비를억제하고있는것으로나타난다. 따라서, 제2형당뇨병에서

6 대한내분비학회지 : 제 25 권제 1 호 2010 Fig. 6. Roles of AMPK in the control of whole-body energy homeostasis. Figure from Kahn et al., 2005[6]. 나타나는당자극에의한인슐린분비저하를개선시키기위해 AMPK를활성화시키기보다는억제시키는것이보다효과적이라고볼수있다. 결론당및지질대사조절의이상등이여러대사성질환의발생에공통적으로관여하는기전으로알려져있다. 최근여러연구들은에너지대사의조절에중추적인역할을담당하는 AMPK[6](Fig. 6) 와대사성질환과의연관성에대해보고하고있으며이러한연구결과들은 AMPK의활성화를조절하는것이비만, 제 2형당뇨병, 고지혈증그리고심혈관계질환등과같은대사성질환의발생을예방하고치료를하는데중요한역할을할수있을것임을제시하고있다. 이에따라앞으로 AMPK를표적으로하는약물개발연구가활발해질것으로전망하고있다. 참고문헌 1. Wing RR, Goldstein MG, Acton KJ, Birch LL, Jakicic JM, Sallis JF Jr, Smith-West D, Jeffery RW, Surwit RS: Behavioral science research in diabetes: lifestyle changes related to obesity, eating behavior, and physical activity. Diabetes Care 24: , Saltiel AR, Kahn CR: Insulin signalling and the regulation of glucose and lipid metabolism. Nature 414: , Towler MC, Hardie DG: AMP-activated protein kinase in metabolic control and insulin signaling. Circ Res 100: , Hardie DG: AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy. Nat Rev Mol Cell Biol 8: , Zhang BB, Zhou G, Li C: AMPK: an emerging drug target for diabetes and the metabolic syndrome. Cell Metab 9: , Kahn BB, Alquier T, Carling D, Hardie DG: AMP-activated protein kinase: ancient energy gauge provides clues to modern understanding of metabolism. Cell Metab 1:15-25, Carling D: The AMP-activated protein kinase cascade--a unifying system for energy control. Trends Biochem Sci 29:18-24, 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 AMP-activated protein kinase. J Biol Chem 271: , Stein SC, Woods A, Jones NA, Davison MD, Carling

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Pharmacotherapeutics Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee Univ

Pharmacotherapeutics Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee Univ Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee University College of Medicine & Hospital E mail : ycell2@yahoo.co.kr Abstract