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1 당뇨병제 30 권제 6 호, 2006 종설 미토콘드리아기능장애와인슐린저항성 울산대학교의과대학서울아산병원내분비내과 조은희 고은희 김민선 박중열 이기업 Mitochondrial Dysfunction and Insulin Resistance Cho EH, Koh EH, Kim MS, Park JY, Lee KU Division of Endocrinology and Metabolism, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine 체내지방의과다축적으로정의되는비만은미용상의문제만이아니라사회, 경제적으로도큰부담이되는질병으로비만에동반되는다른대사성질환인당뇨병, 동맥경화증이크게증가하고있는실정이다. 이와같은질환들 ( 대사증후군 ) 의공통적인원인으로잘알려진것이인슐린저항성이다. 최근미토콘드리아의기능이상이제2형당뇨병, 비만및인슐린저항성과관련됨이알려지면서많은주목을받고있다. 골격근은고인슐린포도당클램프 (euglycemic hyperinsulinemic clamp) 와같은고인슐린혈증상태에서전신포도당이용 / 저장의 70~80% 를차지하는조직이다. 뿐만아니라인슐린저항성상태에서가장뚜렷한포도당이용의감소를보여많은학자들이골격근에서의포도당이용의감소가인슐린저항성의일차적원인이될것으로생각하고있다. 골격근에서의포도당이용의감소는포도당의세포내로의운반과정 (glucose transport), 포도당의인산화과정, 당원으로의합성단계 (glycogen synthesis) 등여러단계의장애에기인할수있는데이중당원합성과정이인슐린저항성상태에서양적으로가장뚜렷하게감소된다 1). 한편골격근에서의포도당운반과정, 당원합성과정등이 insulin receptor substrate-1 (IRS-1) 인산화와 phosphatidyl inositol-3 kinase (PI3K) 와같은세포내인슐린신호전달체계의조절을받고이들신호전달체계의활성이비만및제2형당뇨병환자의골격근에서감소되어있음이여러연구에서밝혀져있다 2). Glucose-fatty acid cycle 1963년 Randle 등은근육내지방산산화의증가가포도당산화를감소시킴을보고하고혈중유리지방산농도의 증가에따른근육내지방산산화의증가가인슐린저항성의원인이됨을제시하였다 (glucose fatty acid cycle) 3). 이가설에의하면지방산산화의증가는미토콘드리아의 acetyl -CoA/CoA 비를증가시켜서피루브산탈수소효소 (pyruvate dehydrogenase) 의활성도를억제함으로써포도당산화를억제하고, 세포내에증가된 citrate는 phosphofructokinase 를억제하여 glucose-6-phosphate의축적을일으킴으로써결과적으로포도당의세포내유입을억제한다는것이다. 이가설은그이후고지방식이나 4) 지방질정맥투여를통한 5) 여러실험을통해증명되었다. 지방산산화의증가가골격근내에서포도당산화의감소를일으킨다는사실은거의모든연구자들에의해확인되었지만실제비만이나당뇨병환자에서보이는인슐린저항성의발생에포도당산화보다더중요한기여를하는당원합성이감소되는지에대해서는논란의여지가있었다. 대부분의초기연구들은혈액내지방산농도를높일경우골격근내포도당산화뿐만아니라당원합성도감소함을보고한반면 Kim 등은고지방식이에의한유리지방산의증가가골격근에서의해당작용을억제시키나 glucose-6 -phosphate 농도및당원합성은오히려증가시킨다고하였다 4). 이와같은 controversy를해결하기위해본교실에서는쥐에지방질을 5시간동안정맥주사하면서시간에따른포도당대사의변화를관찰하였다. 연구에따르면, 지방질투여직후부터포도당산화를대변하는해당작용이뚜렷하게억제되었으나초기에는세포내 glucose-6-phosphate 농도가올라가면서당원합성이보상적으로증가하고이에따라전신및골격근내포도당이용은변하지않았다. 그러나시간이경과함에따라당원합성역시감소하기시작하였고전신포도당이용역시뚜렷하게감소함을보여지방산산화가장기적으로증가할경우당원합성이감소됨을보였다 6)

2 - 당뇨병제 30 권제 6 호, 한편최근의연구들은지방질투여가앞에서기술한 acetyl CoA나 citrate를통해포도당대사이상을초래하는이외에도 PI3K와같은인슐린신호전달체계의변화를유발하여인슐린저항성을유발함을밝히고있다 7). 세포내중성지방및지방산대사산물축적이상혈액내유리지방산의증가가골격근내포도당산화와당원합성을억제하여인슐린저항성을유발한다는사실은믿어의심할여지가없다. 그러나실제혈중지방산농도와인슐린감수성에대한상관계수는 0.6 이하로보고되어왔다. 즉혈중유리지방산의증가만으로는인슐린저항성의발생을충분히설명하지못한다는것이다. 근래에비만한환자나동물모델에서골격근조직내중성지방축적이증가되어있음을알게되었고이로부터혈액내지방산뿐만아니라골격근에저장되어있던중성지방으로부터의국소적인지방분해에의해공급되는지방산역시인슐린저항성발생에중요한역할을할것이라는개념이대두되었다 8). 세포내지방산대사산물인 long-chain fatty acyl-coa (LCAC) 는 glycogen synthase와같은포도당대사효소의활성도를억제하고 protein kinase C나 IkappaB 같은다양한세포내신호전달물질의변화를초래함이밝혀졌고 9), 장기간의운동훈련이나단시간의운동을통해세포내 LCAC 농도를감소시킬경우인슐린감수성이뚜렷하게감소함이밝혀져 10) 세포내 LCAC의축적이인슐린저항성의주원인기전이라는주장이강력하게제기되고있다. 뿐만아니라비만이나당뇨병동물모델에서는혈관조직내에도 중성지방및 LCAC의축적이증가되어있는데, 증가된 LCAC는세포내산화스트레스를증가시킴으로써동맥경화증발생에관여할것이라는가설이제시된바있다 11). 인슐린저항성동물모델에서골격근지방분해의감소이상대사증후군에서골격근이나혈관조직에지방산대사산물이축적되고이로인해인슐린저항성이나동맥경화증이발생할것이라는학설이최근많은학자들의지지를받고있으나이와같은현상이나타나는기전에대한연구는매우부족한상태이다. 골격근세포내에축적된중성지방이세포내에서분해되어지방산산화를촉진시키고이에따라인슐린저항성을유발한다면골격근으로부터의지방분해가증가되어있을것이라고가정할수있을것이다. 그러나본교실에서시행한연구결과 12), 고지방식이를투여한백서에서골격근및지방조직간질의글리세롤농도가기저상태및고인슐린포도당클램프모두에서저지방식이군보다유의하게낮았다 (Fig. 1). 이상의결과는기존의개념과는상반되는것으로인슐린저항성상태에서관찰되는골격근조직내의지방축적증가는세포내에서의지방산산화의감소에의해나타남을시사하고있다. 미토콘드리아와인슐린저항성미토콘드리아는세포내에서대부분의 ATP를생산하는소기관으로이외에도산소라디칼형성, 세포자멸사및세포내칼슘대사등에서중요한역할을한다. ATP의주원료 Fig. 1. Interstitial glycerol concentration in (A) skeletal muscle and (B) adipose tissue under basal and hyperinsulinemic euglycemic clamp conditions, and (C) net change in the interstitial glycerol concentrations during clamp (D) interstitial ethanol concentrations in skletal muscle and adipose tissue during microdialysis 12)

3 - 조은희외 4 인 : 미토콘드리아기능장애와인슐린저항성 - 는포도당과지방산이나특히기저상태의골격근세포에서는주로지방산이이용되기때문에미토콘드리아기능이상이있을경우에는세포내지방산산화가감소하게되고이에따라 LCAC의축적이일어나게된다. 당뇨병에서세포내에너지결핍이나타난다는것은잘알려진사실로미토콘드리아기능과인슐린작용이연관되어있으리라는것을쉽게예상할수있으나, 실제당뇨병과미토콘드리아기능과의관계가알려진것은그리오래되지않았다. 1990년대초미토콘드리아 DNA에돌연변이가있을경우모계로유전되는당뇨병이나타난다는것이처음보고된이후 13) 여러종족에서이사실이확인되었다. 미토콘드리아기능과당뇨병의관계에대해서는 1998년 Lee 등이말초혈액내미토콘드리아의 DNA양이감소가제2형당뇨병발생에선행함을처음보고하였고 14), 이후 Petersen 등은제2형당뇨병환자의자녀에서보이는근육에서의인슐린저항성이근육내지방산대사의이상에의한중성지방의지방내침착과연관이있으며, 주로미토콘드리아의산화적인산화의유전적결함이관여한다고발표하였고 15), 노인환자에서의인슐린저항성은주로미토콘드리아의생성에대한후천적인결함으로근육내미토콘드리아의감소와연관된다고보고하여 16), 미토콘드리아기능저하와인슐린저항성의연관성을제시하였다. PPARα 및 PPARγ 활성제에의한당뇨병발생예방미토콘드리아에서의지방산산화를조절하는인자들로는 PPARα, PPARδ, PPARγ coactivator-1 (PGC-1) 및 AMPK (AMP-activated protein kinase) 등이있다. 이중가장잘알려져있는 PPARα는핵수용체의하나로서활성시지방산수송단백질및 long-chain acyl-coa synthase 발현을유도하여미토콘드리아내로의지방산흡수를증가시키고, acyl-coa oxidase 및 carnitine palmitoyl transferase-1 (CPT-1) 의발현을증가시켜지방산산화를증가시킨다 17). PPARδ는최근큰관심을끌고있는핵수용체로서활성화되면지방산산화가증가되고 adaptive thermogenesis에관련된 uncoupling protein의발현이증가한다 18). PGC-1은미토콘드리아의합성과호흡에관여하는다양한전사조절인자들 (NRF-1,2, mttfa) 의전사활성을촉진시키는 coactivator이며미토콘드리아의 biogenesis, respiration 및 thermogenesis를증가시키는것으로보고되었다 19). 또한갈색지방조직에서의열생산, 근육에서의포도당이용을증가시키는데간에서는 PEPCK 같은포도당신생조절효소를활성화시키는것으로보고되고있다 20). 이외에도핵호르몬수용체인 liver X receptor는지방산합성효소인 fatty acid synthase와지방세포분화에관여하는 SREBP-1의활성을증가시켜지방산산화의 negative regulator로작용할가능성이있다 21). 본교실에서는 PPARα activator인 fenofibrate 및 PPARγ activator인 rosiglitazone이비만및당뇨병모델쥐인 OLETF rats에서당뇨병발생을예방함을발견하였다 22). 알려진바와같이 rosiglitazone 투여군에서는체중증가소견을보였는데이와는반대로 fenofibrate 투여군에서는체중과내장지방의감소를보였다. 지방조직에대한반대효과와는달리두투여군모두골격근에서지방산산화를증가시켰고중성지방축적을감소시켰다. 즉 PPARα뿐만아니라 PPARγ agonist도골격근세포에서지방산산화를증가시킴으로서인슐린감수성의호전을가져옴이시사되었다. AMPK와지방산산화 AMP-activated protein kinase (AMPK) 는세포내에너지상태를감지하는효소로서세포내에너지가부족한상황, 즉 ATP에비해 AMP가증가하는상황에서활성화되어 Alpha-lipoic acid Rosiglitazone Leptin Adiponectin AMPK M itochondrial biogenesis ACC PG C-1/PPAR α Fatty acid oxidation Intracellular Lipid metabolites Insulin resistance Fig. 2. AMPK in fatty acid oxidation and insulin resistance

4 - 당뇨병제 30 권제 6 호, 정상에너지균형을회복시키기위해다양한대사경로를조절한다 23). AMPK는근육에서포도당및지방산대사의중요한조절인자로작용하며, 특히운동을하는근육에서활성화된다 24). 골격근에서 AMPK가활성화되면포도당이용이증가되는이외에도 acetyl CoA carboxylase (ACC) 의인산화를통해 ACC의작용을억제함으로써 malonyl CoA 농도가감소된다. Malonyl CoA는미토콘드리아내로의 LCAC의이송을조절하는 CPT-1을억제하는역할을하는데 AMPK가활성화되어 malonyl CoA가감소되면결과적으로 CPT-1에대한억제효과가감소하게되어지방산산화가증가된다 25). 본교실에서는최근연구에서 C2C12 골격근세포에서 AMPK 활성물질인 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) 가 PPAR-α 목표유전자와 PPARγ coactivator-1 (PGC-1) 의발현을증가시켜지방산산화를증가시키고, PPAR-α와 PGC-1에대한 sirnas처리시 AICAR에의한지방산산화의증가를억제함을보여 26), AMPK가기존의알려진 ACC의작용을억제하는외에도 PPAR-α와 PGC-1를통해서도지방산산화를증가시킴을증명하였다 (Fig. 2). Alpha-lipoic acid (ALA) 와대사증후군 Alpha-lipoic acid (ALA) 는두개의황산분자를포함하는지방산으로미토콘드리아의호흡효소인피루브산탈수소효소 (pyruvate dehydrogenase) 의필수조효소로노화한쥐에서미토콘드리아의기능을호전시키는것으로알려져있다 27). ALA는매우강력한항산화제로주로당뇨병성신경병증의치료제로쓰이는약제이다. 본교실에서는 ALA의장기투여가비만형당뇨병동물모델인 OLETF (Otsuka Long-Evans Tokushima Fatty) 쥐에서당뇨병의발생을예방함을발견하였다. ALA의투여는 OLETF 쥐에서나타나는췌장소도의파괴를억제하였으며, 골격근및췌장소도에서의지방축적을감소시켰다 28). ALA를투여한쥐에서 AMPK 활성도가증가하였고지방산의산화의증가와중성지방축적의감소가관찰되었다 29). 한편 OLETF 쥐에서는대조군에비해혈관내피의존성혈관확장에장애가있고, 내피세포사멸이증가된소견을보였으며, 내피세포내중성지방및 lipid peroxide가증가되어있고, 산화질소 (Nitric oxide) 생산은감소되어있었는데, OLETF 쥐에 ALA를투여시혈관내피의존성혈관확장장애의호전을보였고, 내피세포사멸이억제되었으며, 중성지방의축적과 lipid peroxide는감소시켰으며산화질소는증가되었다 30). 이러한결과를바탕으로 ALA가 AMPK 의활성을증가시키고, 지방산산화를증가시킴으로써 LCAC가감소시킴을알수있었고이기전에의해당뇨병이감소하고, 혈관기능이개선되어동맥경화증이감소함을추론할수있었다. Uncoupling protein-2 (UCP-2) 에의한혈관기능호전미토콘드리아는세포막에있는 NADPH oxidase와함께세포내에서활성산소족 (ROS) 을생산하는제일중요한부위중의하나이다. TCA cycle에의해만들어진 NADH는 NAD+ 로환원되면서 ATP를생산하게된다. 이과정에서미토콘드리아내막의 electron transfer chain을통해전자를이동시키는한편내막및외막사이의 intermembranous space에수소이온 (H + ) 을축적시킴으로써 ATP 생산에필요한에너지를축적시킨다. 이와같이에너지 (mitochondrial membrane potential; MMP) 를축적하는것은 ATP 생산을위한필수적인과정이지만어떠한이유에서든장기적으로증가된 MMP가 ATP 생산과같은과정을통하여해결이되지않을경우에는 electron transfer chain의활동이저해되게되고정상적으로산소와만나물분자가되어야하는전자가 ROS를형성하게된다. Uncoupling protein (UCP) 는갈색지방조직에서처음발견된단백질로서축적된 MMP를 ATP 생산에이용하는대신열로발산시키는기능을가진다. 갈색지방에있는 UCP 이외에도이와유사한물질이다른조직에존재함이알려지고있는데, 그중 uncoupling protein-2 (UCP-2) 는혈관세포를포함한다양한여러조직에서발현된다. UCP-2가혈관기능에미치는영향을확인하기위하여혈관내피세포에과발현시켰을때혈관확장에관여하는 enos (endothelial nitric oxide synthase) 의 mrna 발현이증가하였고, 혈관수축에관여하는 endothelin-1의발현은감소하였다. 또한 UCP-2는혈관내피세포에서 lysophosphatidylcholine이나 linoleic acid에이해유발되는 ROS 증가, NF-kB 활성및세포사멸을억제하였으며이는 UCP-2가혈관내피세포에서 ROS의생성을조절하는중요한역할을함을시사한다 31). 또한혈관평활근세포에서고농도의포도당과안지오텐신 II 를처리하였을때세포내산화스트레스및전사인자 AP-1, PAI-1 발현및 NADPH oxidase가활성화되고동맥경화증의발생지표인혈관평활근세포의증식및이주또한증가하였다. 하지만, UCP-2를혈관평활근세포에과발현시켰을때이러한변화가현저하게억제되는것을관찰할수있었다 32). 이와같은결과는 UCP-2가혈관내피세포에서미토콘드리아의 ROS 생성을조절함으로동맥경화증의발생을줄일수있음을보여주는것으로, 미토콘드리아의기능이상이동맥경화증의발생에연관됨을시사하고있다

5 - 조은희외 4 인 : 미토콘드리아기능장애와인슐린저항성 - M i t o c h o n d r i a l d y s f u n c t i o n in O S E R s t r e s s JN K /A TF3 T r a n s c r i p t i o n P o s t - t r a n s l a t i o n a l m o d i f i c a t i o n A d i p o n e c t i n Fig. 3. Schematic model of the mechanism by which adiponectin synthesis is reduced in obesity. Adipocyte hypertrophy in obesity is associated with mitochondrial dysfunction, and consequent activation of inos and ER stress affect transcription and post-translational modification to result in decreased production of adiponectin. 미토콘드리아와아디포넥틴생산 결 론 최근지방조직이능동적으로호르몬 (adipokine, adipocytokine) 을분비함으로써체내에너지항상성유지에중요한역할을한다는개념이보편화되고있다. 아디포넥틴 (Adiponectin) 은지방세포에서다른 adipokine에비해매우과량으로생산되는물질인데골격근세포나혈관세포에서 AMPK를활성화시켜당뇨병이나동맥경화증발생을예방할수있음이밝혀져큰관심을끌고있다 34,35). 비만환자에서혈액내다른 adipokine 농도는증가하나아디포넥틴농도는역설적으로감소되어있는데, 아직까지이와같은현상이나타나는기전은밝혀져있지않았다. 본교실에서는최근지방세포에서의아디포넥틴생산에미토콘드리아의정상적인기능이필수적임을발견하였고비만쥐의지방세포에서미토콘드리아의양및기능이저하됨을밝힘으로써비만환자에서혈액내아디포넥틴농도가감소되는 paradox를설명할단서를찾았다 ( 미발표자료 ). 배양된지방세포에여러가지미토콘드리아기능저해물질을처리하였을때 inos (inducible nitric oxide synthase) 활성화, endoplasmic reticulum stress, JNK 활성화및 ATF3 발현증가를통해아디포넥틴의전사 (transcription) 가감소하였고, 고분자량아디포넥틴 (high molecular weight adiponectin) 생산도감소하였다. 반면 rosiglitazone이나 nuclear respiratory factor-1 (NRF-1) 에의해미토콘드리아생성을증가시켰을때, 아디포넥틴생산이증가함을보임으로써이제까지알려지지않았던지방세포미토콘드리아기능을처음으로밝혔다 (Fig. 3). 혈액내유리지방산의증가가골격근내포도당산화와당원합성을억제하여인슐린저항성을유발하나, 혈중유리지방산의증가만으로는인슐린저항성의발생을충분히설명하지못한다. 근래비만한환자나동물모델에서골격근조직내중성지방축적이증가되어있음이밝혀졌고이와같은지방축적의증가는세포내에서의지방산산화의감소에의한다고여겨지고있다. 세포내지방산산화의감소로인해대사산물인 long-chain fatty acyl-coa (LCAC) 가축적되고, 이러한 LCAC가 glycogen synthase와같은포도당대사효소의활성도를억제하고 protein kinase C나 IkappaB 같은다양한세포내신호전달물질을변화시켜인슐린저항성을일으킨다고생각되고있다. 미토콘드리아에서지방산산화의대부분이일어나는데, PPARα, PPARδ, PGC-1 및 AMPK 등은지방산산화를증가시켜인슐린감수성을증가시킨다. 한편최근의연구에의해미토코드리아기능이상과 ER stress의연관성이밝혀지고있어, 향후미토콘드리아의기능이상과 ER stress 그리고인슐린저항성에대한좀더많은관심이요구된다. 참고문헌 1. Wright KS, Beck-Nielsen H, Kolterman OG, Mandarino LJ: Decreased activation of skeletal muscle glycogen synthase by mixed-meal ingestion in NIDDM. Diabetes 37:436-46, Kim YB, Nikoulina SE, Ciaraldi TP, Henry RR, Kahn BB: Normal insulin-dependent activation of

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농림수산식품부장관귀하 이보고서를 팥의대사성질환개선및기능성규명 에관한연구의최종보고서로제출 합니다 년 2 월 11 일 - 1 -

농림수산식품부장관귀하 이보고서를 팥의대사성질환개선및기능성규명 에관한연구의최종보고서로제출 합니다. 2013 년 2 월 11 일 - 1 - 연구기관명 : 부산대학교 연구책임자 : 정명호 연구원 : 손용해 연구원 : 장민경 - 2 - Ⅰ. 제목 팥의대사성질환개선및기능성규명 Ⅱ. 연구개발의목적및필요성 팥의대사성질환개선소재발굴과그기능성을과학적으로증명하기위해, 팥의당뇨,