Obesity potentiates development of fatty liver and insulin resistance, but not atherosclerosis, in high-fat diet-fed agouti LDLR-deficient mice
Obesity potentiates development of fatty liver and insulin resistance, but not atherosclerosis, in high-fat diet-fed agouti LDLR-deficient mice
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DOI：
10.1152/ajpendo.00171.2007
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发表时间：
2007-08-01
影响因子：
5.1
通讯作者：
Hasty, Alyssa H.
中科院分区：
文献类型：
--
作者：
Coenen, Kimberly R.;Hasty, Alyssa H.
肥胖正以惊人的速度增长，与之相关的疾病给我们的医疗体系带来了相当大的压力。虽然它们并不总是一致的，但肥胖经常伴有高脂血症。肥胖和高脂血症都与动脉粥样硬化、非酒精性脂肪性肝病（NAFLD）和胰岛素抵抗（IR）独立相关。因此，我们试图确定肥胖和高脂血症对这些相关病理的相对贡献。肥胖豚鼠（A(y)/ A）和它们的同窝对照（A / A）被置于LDL受体（-/-）背景下。4月龄时，小鼠分别饲喂周粮（CD）和西粮（WD） 12周。这些基因和饮食操作产生了四个实验组：1)瘦肉，a/a；LDLR - / - CD;2)基因诱导肥胖（GIO）， A(y)/ A；LDLR - / - CD;3)饮食性肥胖（DIO）， a/a；LDLR - / - WD;4)基因加饮食诱导肥胖（GIO/DIO）， A(y)/ A；LDLR - / - WD。脂蛋白谱显示，与cd喂养的对照组相比，wd喂养的小鼠VLDL和LDL颗粒增加。该小鼠模型中出现的高脂血症是肝脏甘油三酯生成增加和血浆中脂蛋白清除延迟的结果。两个WD喂养组显示出相似水平的动脉粥样硬化病变面积，GIO/DIO组肥胖增加对动脉粥样硬化没有影响。然而，GIO/DIO组的严重肥胖确实加重了NAFLD和IR。这些发现表明，尽管肥胖和高脂血症会产生单独的病理影响，但在该小鼠模型中，两者的结合有可能对NAFLD和IR产生叠加效应，但不会对动脉粥样硬化产生叠加效应。
Obesity is increasing at an alarming rate, and its related disorders are placing a considerable strain on our healthcare system. Although they are not always coincident, obesity is often accompanied by hyperlipidemia. Both obesity and hyperlipidemia are independently associated with atherosclerosis, nonalcoholic fatty liver disease (NAFLD), and insulin resistance (IR). Thus, we sought to determine the relative contributions of obesity and hyperlipidemia to these associated pathologies. Obese agouti (A(y)/a) mice and their littermate controls (a/a) were placed on an LDL receptor (LDLR)(-/-) background. At 4 mo of age, mice were either maintained on chow diet (CD) or placed on Western diet (WD) for 12 wk. These genetic and dietary manipulations yielded four experimental groups: 1) lean, a/a; LDLR-/- CD; 2) genetic-induced obesity (GIO), A(y)/a; LDLR-/- CD; 3) diet-induced obesity (DIO), a/a; LDLR-/- WD; and 4) genetic-plus diet-induced obesity (GIO/DIO), A(y)/a; LDLR-/- WD. Lipoprotein profiles revealed increased VLDL and LDL particles in WD-fed mice compared with CD-fed controls. The hyperlipidemia present in this mouse model was the result of both increased hepatic triglyceride production and delayed lipoprotein clearance from the plasma. Both WD- fed groups exhibited similar levels of atherosclerotic lesion area, with increased obesity in the GIO/DIO group having no impact on atherogenesis. However, the severe obesity in the GIO/DIO group did aggravate NAFLD and IR. These findings suggest that, although obesity and hyperlipidemia exert individual pathological effects, the combination of the two has the potential to exert an additive effect on NAFLD and IR but not atherosclerosis in this mouse model.