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多発性嚢胞腎モデルラットの肝病変に対する長期的運動とメトホルミンの効果

佐藤 陽一 東北大学

2021.03.25

概要

I. 要約背景
 多発性肝嚢胞(polycystic liver disease:PLD)は肝臓に嚢胞と線維化を来す遺伝性疾患であり,現在のところ有効な治療法は確立していない.AMP-activated protein kinase(AMPK)を活性化する作用のあるメトホルミンは腎嚢胞に対して抑制効果があり,肝嚢胞に対しても抑制効果がある可能性がある.同様にAMPKを活性化する長期的運動は,様々な内部障害モデルにおいて臓器保護効果がある.肝疾患モデルにおいても長期的運動の抗炎症効果や抗線維化効果が報告されているが,PLDに対する効果の報告はない.そこで,腎嚢胞とともに肝嚢胞を形成するpoly-cystic kidney(PCK)ラットにおいて,AMPK活性化薬であるメトホルミンと長期的運動の効果を検討した.

方法
 5週齢の雄性PCKラットをメトホルミン群(n=7)と対照群(n=6)に分け,メトホルミン群にはメトホルミン(300mg/kg/day)を12週間経口投与し,介入終了後に肝組織像と細胞増殖・嚢胞液分泌・線維化の調節因子を検討した.また,同週齢の雄性PCKラットを運動群と安静群に無作為に分け,同週齢の雄性Sprague-Dawley(SD)ラットを対照群(各群n=10)とした.運動群には中強度のトレッドミル運動(傾斜角度0°,速度28m/分,60分間/日,5日/週)を12週間実施した.介入前後で心肺運動負荷試験を実施し,介入終了後に肝組織像と細胞増殖・嚢胞液分泌・線維化の調節因子を検討した.

結果
 嚢胞指数,線維化指数,嚢胞周囲のKi-67陽性細胞数は,対照群と比べてメトホルミン群で有意に減少した.AMPKリン酸化は,対照群と比べてメトホルミン群で有意に増加した.細胞増殖を調節するmammalian target of rapamycin(mTOR)とextracellular signal-regulated kinase(ERK)のリン酸化,嚢胞液分泌を調節するcystic fibrosis transmembrane conductance regulator(CFTR)とaquaporin 1(AQP1)の蛋白発現は,対照群と比べてメトホルミン群で有意に減少した.線維化を調節するtransforming growth factor - β(TGF-β)とType1collagen(COL1)の蛋白発現は,対照群と比べてメトホルミン群で有意に減少した.
 長期的運動の介入前では,SDラットと比べてPCKラットで運動耐容能の低下を認めた.12週間の介入後の運動耐容能は,安静群と比べて運動群で有意に高かった.肝重量や嚢胞指数,線維化指数,Ki-67陽性細胞数は,安静群と比べて運動群で有意に減少した.AMPKリン酸化は,安静群と比べて運動群で有意に増加し,mTORとERKのリン酸化,CFTR,AQP1,TGF-β,COL1の蛋白発現は,安静群と比べて運動群で有意に減少した.

結論
 PCKラットにおいて,長期的運動とメトホルミンは共にAMPKをリン酸化し、胆管上皮細胞の過剰増殖の抑制,嚢胞液異常分泌や線維化調節因子の低下を伴って,肝嚢胞増大や肝線維化を抑制する.長期的運動のPLD進行抑制には,AMPK活性化が関与することが示唆される.

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