2015年5月12日訊 /生物谷BIOON/ --許多研究發現蛋白質高度乙醯化與葡萄糖不耐受和胰島素抵抗之間具有一定關聯性，這表明調節乙醯化修飾組的酶可能在糖代謝的病理學過程中發揮重要作用。近日，來自美國的科學家在國際學術期刊diabetes在線發表了一項最新科研進展，他們發現去乙醯化酶sirt3在促進機體對葡萄糖的處理，增強線粒體功能，改善飲食誘導的胰島素抵抗方面具有重要作用。
Sirt3是定位於線粒體中的NAD+依賴性去乙醯化酶，之前有研究發現sirt3在調節能量平衡方面具有重要作用。因此，在該項研究中，研究人員提出重要假設，通過基因刪除sirt3造成線粒體蛋白乙醯化修飾水平的紊亂，可能會促進高脂飲食誘導的不良效應。
研究人員利用高胰島素－正葡萄糖鉗夾術實驗首次發現由於骨骼肌葡萄糖攝取缺陷，導致sirt3缺失小鼠表現出胰島素抵抗增加。隨後，研究人員利用高脂飲食餵養的sirt3敲除小鼠肌肉纖維進行研究發現基於三羧酸循環底物的呼吸作用下降，而基於脂肪酸的呼吸作用增強，這表明細胞發生從以葡萄糖為能源向以脂肪酸為能源的轉變。伴隨著高脂飲食餵養的sirt3敲除小鼠骨骼肌葡萄糖攝取能力減弱，結合到線粒體的己糖激酶II（HKII）也發生減少，說明HKII活性出現下降。
這些結果表明在高脂飲食誘導的小鼠模型中，sirt3缺失會引起胰島素刺激的骨骼肌葡萄糖攝取能力減弱，導致骨骼肌細胞對脂肪酸的依賴性增加，但在sirt3敲除的瘦小鼠中，胰島素的作用並未受到損傷。
這項研究表明骨骼肌中的去乙醯化酶sirt3對於骨骼肌響應胰島素作用以及改善高脂飲食誘導的胰島素抵抗具有重要作用。（生物谷Bioon.com）
SIRT3 is crucial for maintaining skeletal muscle insulin action and protects against severe insulin resistance in high fat fed mice
Louise Lantier, Ashley S. Williams1, Ian M. Williams1, Karen K. Yang1, Deanna P. Bracy1, Mickael Goelzer1, Freyja D. James1, David Gius3 and David H. Wasserman
Protein hyperacetylation is associated with glucose intolerance and insulin resistance suggesting that the enzymes regulating the acetylome play a role in this pathological process. SIRT3, the primary mitochondrial deacetylase, has been linked to energy homeostasis. Thus, it is hypothesized that the dysregulation of the mitochondrial acetylation state, via genetic deletion of SIRT3, will amplify the deleterious effects of a high fat diet (HFD). Hyperinsulinemic-euglycemic clamp experiments show, for the first time, that mice lacking SIRT3 exhibit increased insulin resistance due to defects in skeletal muscle glucose uptake. Permeabilized muscle fibers from HF-fed SIRT3 KO mice showed that TCA cycle substrate-based respiration is decreased while fatty acid-based respiration is increased, reflecting a fuel switch from glucose to fatty acids. Consistent with reduced muscle glucose uptake, hexokinase II (HKII) binding to the mitochondria is decreased in muscle from HF-fed SIRT3 KO mice, suggesting decreased HKII activity. These results show that absence of SIRT3 in HF-fed causes profound impairments in insulin-stimulated muscle glucose uptake, creating an increased reliance on fatty acids. Insulin action was not impaired in the lean SIRT3 KO mice. This suggests that SIRT3 protects against dietary insulin resistance by facilitating glucose disposal and mitochondrial function.