Dyslipidemia, steatohepatitis and atherogenesis in lipodystrophic apoE deficient mice with Seipin deletion
Dyslipidemia, steatohepatitis and atherogenesis in lipodystrophic apoE deficient mice with Seipin deletion
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Seipin 缺失的脂肪营养不良 apoE 缺陷小鼠的血脂异常、脂肪性肝炎和动脉粥样硬化
DOI：
10.1016/j.gene.2018.01.062
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发表时间：
2018-03-30
期刊：
影响因子：
3.5
通讯作者：
Liu, George
中科院分区：
文献类型：
--
作者：
Liao, Jiawei;Liu, Xuejing;Liu, George
SEIPIN是一种位于内质网的完整膜蛋白，调节脂肪细胞分化和脂肪分解。小鼠缺乏Seipin导致严重的全身脂肪营养不良，并伴有胰岛素抵抗、餐后高甘油三酯血症和脂肪性肝炎。在动脉粥样硬化易发的Ldlr缺失（Ldlr(-/-)）小鼠中，当使用致动脉粥样硬化饮食时，由Seipin缺失引起的脂肪营养不良甚至导致严重的高胆固醇血症和加速动脉粥样硬化。然而，在Seipin(-/-) (-)Ldlr(-/-) ice中观察到的表型是否是由于脂肪营养不良引起的常见结果，而不是遗传背景限制或饮食依赖，尚不清楚。在这里，我们在另一种动脉粥样硬化易感性小鼠模型——载脂蛋白E缺失（apoE(-/-)）小鼠中探讨了与脂肪营养不良相关的血脂异常、脂肪性肝炎和动脉粥样硬化。此外，我们还比较了Seipin缺失的apoE（-/-）小鼠(Seipin（-/-) apoE(-/-)）的两性表型。我们发现，与apoE（-/-）对照相比，Seipin(-/-) apoE（-/-）组也出现了严重的全面性脂肪营养不良，伴有高脂血症、脂肪性肝炎和动脉粥样硬化增加。尽管雌性和雄性Seipin(-/-) apoE（-/-）小鼠脂肪损失的严重程度相似，但雌性高脂血症、脂肪性肝炎和动脉粥样硬化的严重程度低于雄性。因此，我们在Ldlr（-/-）和apoE（-/-）小鼠中发现，由Seipin缺失引起的脂质营养不良相关代谢紊乱与遗传背景和实验饮食无关。然而，性别因素影响了疾病的进展，女性更不易发生与脂肪营养不良相关的代谢后果。
SEIPIN is an integral membrane protein located in the endoplasmic reticulum, regulating adipocytes differentiation and lipolysis. Deficiency of Seipin in mice causes severe general lipodystrophy, accompanied by insulin resistance, postprandial hypertriglyceridemia and steatohepatitis. In atherosclerosis-prone Ldlr null (Ldlr(-/-)) mice, lipodystrophy caused by Seipin deletion even led to severe hypercholesteremia and accelerated atherogenesis, when challenged with an atherogenic diet. However, whether the phenotypes observed in Seipin(-/-) (-)Ldlr(-/-) ice were a common consequence due to lipodystrophy, rather than genetic background restricted or diet dependent, was unknown. Herein we explored the lipodystrophy-related dyslipidemia, steatohepatitis and atherogenesis in another atherosclerosis-prone murine model, apolipoprotein E null (apoE(-/-)) mice. Besides, we also compared phenotypes between sexes in apoE(-/-) mice with Seipin deletion (Seipin(-/-) apoE(-/-)). We found that compared with apoE(-/-) controls, Seipin(-/-) apoE(-/-) ice also developed severe general lipodystrophy with hyperlipidemia, steatohepatitis and increased atherogenesis. Although the severity of adipose loss in female and male Seipin(-/-) apoE(-/-) mice were similar, hyperlipidemia, steatohepatitis and atherosclerosis were less severe in females than in males. Therefore, we demonstrated that lipodystrophy-related metabolic disorders, caused by Seipin deletion, were independent of genetic background and experimental diet, as seen in Ldlr(-/-) and apoE(-/-) mice. However, gender factor affected the disease progression, with females more resistant to developing lipodystrophy-related metabolic consequences.