硫辛酸抑制第二型糖尿病大鼠肝臟NLRP3發炎體活化及非酒精性脂肪肝生成之研究
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2019
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近來研究證實第二型糖尿病(T2DM)與非酒精性脂肪肝(NAFLD)之間有相當大的關聯性，T2DM胰島素阻抗導致的肝臟NLRP3發炎體活化可能與脂肪堆積有關。α-硫辛酸(ALA)已被報導可改善T2DM大鼠胰島素阻抗和肝臟發炎。本研究探討ALA對高脂飲食(HFD)及鍊脲佐菌素(STZ)誘發T2DM大鼠肝臟中NLRP3發炎體活化、胰島素阻抗及脂肪堆積的影響。八周大的雄性Wistar大鼠以HFD (60%脂肪)餵養4周後，腹腔注射(ip)低劑量STZ (30mg/kg bw)並繼續餵食HFD巴已以後成功誘導第二型糖尿病，之後每日管餵ALA (50、100、200 mg/kg bw) 13周後，犧牲大鼠並採集血液進行分析、以西方墨點法(Western blot)測量大鼠肝臟胰島素阻抗、NLRP3發炎體相關蛋白質、細胞激素IL-1β及脂肪代謝相關蛋白質表現量，並檢測肝臟中三酸甘油酯(TG)的濃度。結果顯示，給予ALA 50、100、200 mg/kg bw處理能夠顯著降低HFD/STZ誘導T2DM大鼠肝臟之TG含量，與DM組相比分別降低61.8%、71.1%、64.7%。此外，給予ALA 200mg/kg bw能夠顯著提升T2DM大鼠肝臟胰島素傳訊相關路徑蛋白質PI3K以及pAkt/Akt表現量170.3%、100.3%，並降低肝臟NLRP3發炎體上游之NLRP3蛋白71.1%、降低下游caspase-1、IL-1β蛋白表現量52.3%、34.21%和降低脂肪合成相關蛋白質SREBP-1c之表現量48.1%、並增加脂肪氧化酵素CPT-1表現量47.1%此外，給予ALA 200mg/kg bw能夠顯著提升T2DM大鼠肝臟胰島素傳訊相關路徑蛋白質PI3K以及pAkt/Akt表現量170.3%、100.3%，並降低肝臟NLRP3發炎體上游之NLRP3蛋白71.1%、降低下游caspase-1、IL-1β蛋白表現量52.3%、34.21%和降低脂肪合成相關蛋白質SREBP-1c之表現量48.1%、並增加脂肪氧化酵素CPT-1表現量47.1%。歸納上述研究結果，給予ALA處理能夠改善HFD/STZ誘導T2DM大鼠肝臟胰島素阻抗、發炎體活化及脂肪堆積之惡性循環。本實驗結果可作為未來評估ALA開發為預防糖尿病所引發NAFLD合併症的膳食補充劑或保健食品之參考。
Recently studies suggested that there is correlation between type 2 diabetes (T2DM) and nonalcoholic fatty liver disease (NAFLD). Liver NLRP3 inflammasome activation caused by insulin resistance may be associated with fat accumulation. Alpha-lipoic acid (ALA) has been reported to improve insulin resistance and reduce liver inflammation in T2DM rats. The present work was to investigate the effects of ALA on NLRP3 inflammasome activation, insulin resistance and fat accumulation of liver in high-fat diet plus streptozotocin (STZ) induced T2DM rats. Male Wistar rats fed with HFD (60% fat) for 4 weeks, and intraperitoneal (ip) low-dose STZ (30 mg/kg bw) and continued feeding of HFD until induced type 2 diabetes. After 13 weeks of feeding ALA (50, 100, 200 mg/kg bw), the rats were sacrificed and blood was collected for analysis. The insulin resistance, NLRP3 inflammasome related protein in liver was measured by Western blot. The content of IL-1β and the concentration of triglyceride (TG) in the liver was measured. The results showed that treatment with ALA 50, 100, 200 mg/kg bw significantly reduced the TG content in the liver of T2DM rats induced by HFD/STZ, which was 61.8%, 71.1%, and 64.7% lower than the DM group. In addition, the group of ALA 200mg/kg bw significantly increased the protein expression of PI3K and pAkt/Akt in the liver compared with DM rats which take up 170.3%, 100.3%, and decreased the NLRP3 inflammasome relative protein NLRP3, caspase-1, IL-1β expression by 71.1%, 52.3% and 34.21%. The expression of SREBP-1c, a protein related to fat synthesis, was decreased by 48.1%, and the expression of CPT-1 was increased by 47.1%. In conclusion, ALA treatment alleviated the hepatic insulin resistance, inflammasome activation and fat accumulation in HFD/STZ-induced T2DM rats. The results of this study suggest ALA as a health supplements in NAFLD complications caused by diabetes.
Recently studies suggested that there is correlation between type 2 diabetes (T2DM) and nonalcoholic fatty liver disease (NAFLD). Liver NLRP3 inflammasome activation caused by insulin resistance may be associated with fat accumulation. Alpha-lipoic acid (ALA) has been reported to improve insulin resistance and reduce liver inflammation in T2DM rats. The present work was to investigate the effects of ALA on NLRP3 inflammasome activation, insulin resistance and fat accumulation of liver in high-fat diet plus streptozotocin (STZ) induced T2DM rats. Male Wistar rats fed with HFD (60% fat) for 4 weeks, and intraperitoneal (ip) low-dose STZ (30 mg/kg bw) and continued feeding of HFD until induced type 2 diabetes. After 13 weeks of feeding ALA (50, 100, 200 mg/kg bw), the rats were sacrificed and blood was collected for analysis. The insulin resistance, NLRP3 inflammasome related protein in liver was measured by Western blot. The content of IL-1β and the concentration of triglyceride (TG) in the liver was measured. The results showed that treatment with ALA 50, 100, 200 mg/kg bw significantly reduced the TG content in the liver of T2DM rats induced by HFD/STZ, which was 61.8%, 71.1%, and 64.7% lower than the DM group. In addition, the group of ALA 200mg/kg bw significantly increased the protein expression of PI3K and pAkt/Akt in the liver compared with DM rats which take up 170.3%, 100.3%, and decreased the NLRP3 inflammasome relative protein NLRP3, caspase-1, IL-1β expression by 71.1%, 52.3% and 34.21%. The expression of SREBP-1c, a protein related to fat synthesis, was decreased by 48.1%, and the expression of CPT-1 was increased by 47.1%. In conclusion, ALA treatment alleviated the hepatic insulin resistance, inflammasome activation and fat accumulation in HFD/STZ-induced T2DM rats. The results of this study suggest ALA as a health supplements in NAFLD complications caused by diabetes.
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第二型糖尿病, 非酒精性脂肪肝, 胰島素阻抗, α-硫辛酸, type 2 diabetes, nonalcoholic fatty liver, insulin resistance, alpha-lipoic acid