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
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 respons e element binding protein ( ChREBP ) 、 peroxisome proliferator activated receptor-??/?? ( PPAR-α 、 PPA R-?? ) 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-meth ylglutaryl coenzyme A reductase ( HMG-CoA reductase ) 、肝臟膽固醇代謝酵素 cholesterol 7??-hydroxyl ase 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。
Effects of Rice Bran Oil on Insulin Sensitivity and Hepatic Lipid Metabolism in Type 2 Diabetic Rats
The hypolipidemic and hypocholesterolic effects of rice bran oil (RO) consumption have been established in several hyperlipi demic 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 ef fects of RO consumption on the expression of hepatic enzymes that influence cholesterol metabolism, streptozotocin/nicotina mide-induced type 2 diabetic rats were fed high-fat diets composed of 0, 10, and 15% RO for 4 weeks (Study 1). The effects o f the RO consumption on insulin resistance in vivo and the protein expression of the hepatic enzymes that control lipid, glucos e, and cholesterol metabolism were analyzed in type 2 diabetic rats that were fed a high-fat diet composed of 15% RO for 4 w eeks ( Study 2 ). In addition, in study 2, the effects of RO consumption on sterol regulatory element binding protein-1c/2 ( SR EBP-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 regu lating 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. Finall y, RO consumption increased excretion of fecal bile acids and neural sterols. In study 2, RO consumption increased expressio n of SREBP-1c and SREBP-2 transcription factors, which further increased hepatic acetyl-CoA carboxylase, fatty acid syntha se, HMG-CoA reductase, cholesterol 7??-hydroxylase, LDL-receptor, and glucokinase protein and mRNA expression in diabe tic rats. After RO consumption, increased excretion of fecal bile acids and neural sterols were detected in diabetic rats. In addt ion, intraperitoneal glucose tolerance tests and analysis of the muscular insulin receptor and PPAR-?? protein expression reve aled that ingestion of RO improved the insulin sensitivity in diabetic rats. In conclusions, ingestion of RO depletes the cholest erol pool in vivo and further affects SREBP-1c and SREBP-2 expression, resulting in altered mRNA and protein expression o f 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 an d hyperlipidemia in type 2 diabetic rats.
