Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06536-8012, USA.
Hepatology. 2011 Nov;54(5):1650-60. doi: 10.1002/hep.24571. Epub 2011 Aug 19.
Nonalcoholic fatty liver disease (NAFLD) and insulin resistance have recently been found to be associated with increased plasma concentrations of apolipoprotein CIII (APOC3) in humans carrying single nucleotide polymorphisms within the insulin response element of the APOC3 gene. To examine whether increased expression of APOC3 would predispose mice to NAFLD and hepatic insulin resistance, human APOC3 overexpressing (ApoC3Tg) mice were metabolically phenotyped following either a regular chow or high-fat diet (HFD). After HFD feeding, ApoC3Tg mice had increased hepatic triglyceride accumulation, which was associated with cellular ballooning and inflammatory changes. ApoC3Tg mice also manifested severe hepatic insulin resistance assessed by a hyperinsulinemic-euglycemic clamp, which could mostly be attributed to increased hepatic diacylglycerol content, protein kinase C-ϵ activation, and decreased insulin-stimulated Akt2 activity. Increased hepatic triglyceride content in the HFD-fed ApoC3Tg mice could be attributed to a ≈ 70% increase in hepatic triglyceride uptake and ≈ 50% reduction hepatic triglyceride secretion.
These data demonstrate that increase plasma APOC3 concentrations predispose mice to diet-induced NAFLD and hepatic insulin resistance.
非酒精性脂肪性肝病（NAFLD）和胰岛素抵抗最近被发现与携带载脂蛋白 CIII（APOC3）基因胰岛素反应元件内单核苷酸多态性的人类血浆中载脂蛋白 CIII（APOC3）浓度升高有关。为了研究 APOC3 表达增加是否会使小鼠易患 NAFLD 和肝胰岛素抵抗，在给予常规饮食或高脂肪饮食（HFD）后，对载脂蛋白 CIII 过表达（ApoC3Tg）小鼠进行了代谢表型分析。在 HFD 喂养后，ApoC3Tg 小鼠肝甘油三酯蓄积增加，这与细胞气球样变和炎症改变有关。通过高胰岛素-正常血糖钳夹术评估，ApoC3Tg 小鼠还表现出严重的肝胰岛素抵抗，这主要归因于肝二酰甘油含量增加、蛋白激酶 C-ε 激活和胰岛素刺激的 Akt2 活性降低。在 HFD 喂养的 ApoC3Tg 小鼠中，肝甘油三酯含量的增加可归因于肝甘油三酯摄取增加约 70%，肝甘油三酯分泌减少约 50%。
这些数据表明，血浆 APOC3 浓度升高使小鼠易患饮食诱导的 NAFLD 和肝胰岛素抵抗。
