Coenen Kimberly R, Hasty Alyssa H
Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, Tennessee 37232-0615, USA.
Am J Physiol Endocrinol Metab. 2007 Aug;293(2):E492-9. doi: 10.1152/ajpendo.00171.2007. Epub 2007 Jun 12.
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.
肥胖正以惊人的速度增长，其相关疾病给我们的医疗系统带来了相当大的压力。虽然肥胖与高脂血症并不总是同时出现，但肥胖常伴有高脂血症。肥胖和高脂血症均独立与动脉粥样硬化、非酒精性脂肪性肝病（NAFLD）和胰岛素抵抗（IR）相关。因此，我们试图确定肥胖和高脂血症对这些相关病理状况的相对影响。将肥胖的刺豚鼠（A(y)/a）小鼠及其同窝对照（a/a）置于低密度脂蛋白受体（LDLR）基因敲除背景下。4月龄时，将小鼠分为两组，一组维持普通饮食（CD），另一组给予西式饮食（WD），持续12周。这些基因和饮食干预产生了四个实验组：1）瘦型，a/a;LDLR(-/-)CD；2）基因诱导肥胖（GIO），A(y)/a;LDLR(-/-)CD；3）饮食诱导肥胖（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，与喂食CD的对照相比，喂食WD的小鼠极低密度脂蛋白（VLDL）和低密度脂蛋白（LDL）颗粒增加。该小鼠模型中的高脂血症是肝脏甘油三酯生成增加和血浆脂蛋白清除延迟共同作用的结果。两个喂食WD的组动脉粥样硬化病变面积水平相似，GIO/DIO组肥胖增加对动脉粥样硬化形成没有影响。然而，GIO/DIO组的严重肥胖确实加重了NAFLD和IR。这些发现表明，虽然肥胖和高脂血症各自产生病理影响，但在该小鼠模型中，两者的联合作用可能对NAFLD和IR产生叠加效应，但对动脉粥样硬化没有影响。
