米麩油對第 2 型糖尿病大鼠體內胰島素敏感性與肝臟脂質代謝之影
響
Effects of Rice Bran Oil on Insulin Sensitivity and Hepatic Lipid
Metabolism in Type 2 Diabetic Rats
中文摘要 許多關於高脂血症的動物及人體研究報告，均指出攝取米麩油可顯著降低血漿膽 固醇及三酸甘油酯濃度，但是對於給予米麩油的介入對體內血脂代謝相關酵素表 現的調控機轉，以及對第2 型糖尿病的影響，目前尚未完全釐清。本論文研究以 nicotinamide / streptozotocin 誘發第 2 型糖尿病大鼠模式進行實驗，在實驗一中以 0 %、10 % 及 15 % 米麩油含量的高油飼料餵養糖尿病大鼠四週，探討攝取米麩 油對肝臟膽固醇代謝作用相關酵素mRNA 表現的影響。在實驗二則以含 15 % 米 麩油之高油飼料餵養糖尿病大鼠四週，探討攝取米麩油對體內胰島素阻抗現象及 肝臟膽固醇、脂質、葡萄糖代謝作用相關酵素和肌肉胰島素接受體蛋白質和 mRNA 表現的影響。並且更深入探討攝取米麩油是否會改變轉錄因子 sterol regulatory element bindg protein-1c / 2 ( SREBP-1c、SREBP-2 )、carbohydrate response element binding protein ( ChREBP )、peroxisome proliferator activated receptor-??/?? ( PPAR-α、PPAR-?? ) 的表現，進而影響體內脂質代謝、糖質新生 作用與葡萄糖利用等相關蛋白質的表現。
從實驗一的結果發現，第2 型糖尿病大鼠以米麩油實驗飼料餵養四週後會降低禁 食胰島素、血漿三酸甘油酯、低密度脂蛋白膽固醇與肝臟三酸甘油酯含量；並增 加肝臟膽固醇合成酵素3-hydroxy-3-methylglutaryl coenzyme A reductase
( HMG-CoA reductase )、肝臟膽固醇代謝酵素 cholesterol 7??-hydroxylase 與肝臟 low density lipoprotein-receptor ( LDL-receptor ) 的 mRNA 表現，增加肝臟膽固醇 合成與代謝，造成糞便中性固醇及膽酸排出量增加，也首次發現米麩油可改善糖 尿病大鼠的胰島素阻抗。在實驗二的研究結果中，第2 型糖尿病大鼠以 15 % 米 麩油的實驗飼料餵養四週後，發現會增加轉錄因子SREBP-1c、SREBP-2 的表現， 並增加肝臟脂質合成酵素acetyl-CoA carboxylase、fatty acid synthase，以及 HMG-CoA reductase、cholesterol 7??-hydroxylase、LDL-receptor 和 glucokinase 的 蛋白質與mRNA 表現，造成糞便中性固醇及膽酸排出量增加。此外，從腹腔注 射葡萄糖耐受試驗，與肌肉葡萄糖利用蛋白質insulin receptor 與肌肉轉錄因子 PPAR-?? 的表現結果，更證實攝取米麩油可以顯著改善糖尿病大鼠體內的胰島 素阻抗現象。總結研究結果得知，攝取米麩油後會經由降低體內膽固醇儲存量， 增加肝臟轉錄因子SREBP-1c、SREBP-2 的表現，進而改變體內血脂代謝與葡萄 糖利用蛋白質的表現，來增加糞便中性固醇與膽酸排出量，以及降低肌肉轉錄因 子PPAR-?? 的表現，最後達到改善第 2 型糖尿病大鼠的胰島素敏感性及高血脂
症狀。 英文摘要
The hypolipidemic and hypocholesterolic effects of rice bran oil (RO) consumption have been established in several hyperlipidemic animal and human studies. However, the regulatory mechanism by which RO affects lipid metabolic enzymes, as well as the effects of RO on insulin resistance and hyperglycemia in type 2 diabetes remains largely unknown. To investigate the effects of RO consumption on the expression of hepatic enzymes that influence cholesterol metabolism,
streptozotocin/nicotinamide-induced type 2 diabetic rats were fed high-fat diets composed of 0, 10, and 15% RO for 4 weeks (Study 1). The effects of the RO consumption on insulin resistance in vivo and the protein expression of the hepatic enzymes that control lipid, glucose, and cholesterol metabolism were analyzed in type 2 diabetic rats that were fed a high-fat diet composed of 15% RO for 4 weeks ( Study 2 ). In addition, in study 2, the effects of RO consumption on sterol regulatory
element binding protein-1c/2 ( SREBP-1c/2 ), carbohydrate response element binding protein ( ChREBP ), and peroxisome proliferator activated receptor-??/??
( PPAR-α/?? ), which are transcription factors that influence the expression of the hepatic enzymes and muscular proteins regulating glucose uptake, was analyzed. In study 1, RO decreased fasting plasma insulin, triglyceride and LDL cholesterol levels in diabetic rats fed high-fat diet. In addition, RO consumption decreased hepatic triglyceride levels and increased 3-hydroxyl-3- methyl-glutaryl-CoA ( HMG-CoA ) reductase, cholesterol 7??- hydroxylase, and LDL - receptor mRNA expression. Finally, RO consumption increased excretion of fecal bile acids and neural sterols. In study 2, RO consumption increased expression of SREBP-1c and SREBP-2
transcription factors, which further increased hepatic acetyl-CoA carboxylase, fatty acid synthase, HMG-CoA reductase, cholesterol 7??-hydroxylase, LDL-receptor, and glucokinase protein and mRNA expression in diabetic rats. After RO consumption, increased excretion of fecal bile acids and neural sterols were detected in diabetic rats. In addtion, intraperitoneal glucose tolerance tests and analysis of the muscular insulin receptor and PPAR-?? protein expression revealed that ingestion of RO improved the insulin sensitivity in diabetic rats. In conclusions, ingestion of RO depletes the cholesterol pool in vivo and further affects SREBP-1c and SREBP-2 expression, resulting in altered mRNA and protein expression of lipid and cholesterol metabolic enzymes in liver, and increases excretion of fecal bile acids and neural sterols.
Furthermore, RO consumption decreases the expression of muscular PPAR-??. Finally, RO consumption improves the insulin resistance and hyperlipidemia in type 2 diabetic rats.
