運動抑制NF-κB活化調控發炎路徑對糖尿病db/db小鼠肝臟功能之影響

Abstract

肝臟代謝失衡導致脂質異常堆積常在II型糖尿病症下觀察到，肝臟脂質的堆積會使肝細胞氧化壓力上升，並誘發發炎路徑IκB-α/NF-κB活化。過度活化發炎路徑會使體內促發炎細胞激素TNF-α與IL-6濃度上升，最終導致肝臟發炎與肝細胞損傷。長期運動訓練有助於改善肝臟的代謝壓力，減少肝臟脂質堆積並延緩糖尿病脂肪肝病的惡化。目前運動訓練調控能量代謝路徑影響IκB-α/NF-κB發炎訊號路徑的相互關聯仍尚未釐清，因此本研究目的在探討耐力運動訓練調控肝臟能量代謝路徑及發炎路徑對糖尿病小鼠肝臟功能的影響。方法：將16隻5週齡糖尿病db/db小鼠隨機分配到控制組與運動組。運動組進行8週的跑步訓練(跑步速度5.2 m/min，每次60分鐘，每週5次)，控制組不進行任何跑步訓練，於訓練結束後犧牲並取出肝臟，以西方墨點法(Western blot analyses)分析IκB-α/NF-κB發炎路徑與Sirt1/AMPK-α/PGC1-α能量代謝路徑蛋白表現、測量ALT、AST肝臟功能指標及肝臟組織病理切片觀察。結果：組織病理切片結果顯示，8週的耐力運動訓練後，糖尿病db/db小鼠肝臟脂質脂質空泡明顯減少。Sirt1/AMPK-α/PGC1-α蛋白活性顯著提高(P<0.05)，另外IκB-α/NF-κB蛋白磷酸化，則在運動訓練後也顯著提高(P<0.05)。然而肝功能的指標ALT與AST活性則在運動訓練後顯著下降(P<0.05)。結論：本研究結果證實耐力運動訓練有助於改善db/db小鼠肝臟能量代謝的失衡，達到減少肝臟脂質堆積的作用。Hepatic lipid accumulation induced by metabolic dysfunction was accompanied with type II diabetes. Increased intrahepatic lipid content triggers oxidative stress, thus activating IκB-α/NF-κB pathway. Furthermore, activation of the inflammatory pathway and increases in circulating TNF-α and IL-6 levels cause liver damage. The purpose of this study was to determine whether exercise training upregulates the energy metabolism pathway and inhibits inflammatory pathway, thereby alleviating hepatic lipid accumulation and injury. Methods: Eight weeks moderate-intensity exercise (5m/min, 60min/day, and 5days/week for a total of 8weeks) on the Sirt1/AMPK-α/PGC1-α axis and NF-B pathway were investigated in liver of diabetic db/db (C57BL/KsJ-leprdb/leprdb) mice. The statistical significance of the differences between two groups was determined by independent sample t-test (P< 0.05). Results Upregulation of SIRT1 and PGC1-α expression and AMPK activity were observed in db/db mice with exercise training. Decreases in phosphorylation of IB and NF-B were observed in db/db mice with training compared with untrained mice. Conclusion Aerobic exercise training inhibits NFB signaling pathway and activates SIRT1/AMPK pathway, thereby alleviating hepatic lipid accumulation and injury.