Severe hypercholesterolemia, hypertriglyceridemia, and atherosclerosis in mice lacking both leptin and the low density lipoprotein receptor
Severe hypercholesterolemia, hypertriglyceridemia, and atherosclerosis in mice lacking both leptin and the low density lipoprotein receptor
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DOI：
10.1074/jbc.m010176200
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发表时间：
2001-10-05
影响因子：
4.8
通讯作者：
Yamada, N
中科院分区：
文献类型：
--
作者：
Hasty, AH;Shimano, H;Yamada, N
瘦素缺陷小鼠（ob/ob）是肥胖、胰岛素抵抗和糖尿病的优秀小鼠模型，所有这些都是多危险因素综合征的组成部分，与高胆固醇血症一起，会导致动脉粥样硬化的潜在高风险。在当前的研究中，我们发现在低密度脂蛋白受体（LDLR）缺陷（-/-）背景下，ob/ob 小鼠出现了出乎意料的严重高脂血症。双突变小鼠 (LDLR-/-; ob/ob) 在 3-4 个月时血浆总胆固醇 (TC) 和甘油三酯 (TG) 水平显着升高（分别为 1715 +/- 87 和 1016 +/- 172 mg/dl），导致 6 个月时整个主动脉出现广泛的动脉粥样硬化病变。脂蛋白分析显示，TC 和 TG 水平升高是由于含有 apoB 的宽 β 残余脂蛋白部分大幅增加。虽然禁食、饮食限制和低水平瘦素治疗显着降低了 TG 水平，但它们仅引起 TC 水平的轻微变化。肝脏胆固醇和甘油三酯含量以及胆固醇生成和脂肪生成酶的 mRNA 水平表明，瘦素缺乏会增加肝脏甘油三酯的产生，但不会改变 ob/ob 小鼠的胆固醇产生，无论其 LDLR 基因型如何。这些数据提供了证据，表明双突变小鼠中的高甘油三酯血症和高胆固醇血症是由不同的机制引起的，并指出瘦素可能对血浆胆固醇代谢产生一些影响，可能是通过不依赖于 LDLR 的途径。该模型将成为未来研究燃料代谢受损、血浆残余脂蛋白增加、糖尿病和动脉粥样硬化之间关系的绝佳工具。
Leptin-deficient mice (ob/ob) are an excellent murine model for obesity, insulin resistance, and diabetes, all of which are components of a multiple risk factor syndrome that, along with hypercholesterolemia, precipitates a potential high risk for atherosclerosis. In the current study, we show an unexpectedly severe hyperlipidemia in ob/ob mice on a background of low density lipoprotein receptor (LDLR) deficiency (-/-). Doubly mutant mice (LDLR-/-; ob/ob) exhibited striking elevations in both total plasma cholesterol (TC) and triglyceride (TG) levels (1715 +/- 87 and 1016 +/- 172 mg/dl, respectively), at age 3-4 months, resulting in extensive atherosclerotic lesions throughout the aorta by 6 months. Lipoprotein analyses revealed the elevated TC and TG levels to be due to a large increase in an apoB-containing broad-beta remnant lipoprotein fraction. While fasting, diet restriction, and low level leptin treatment significantly lowered TG levels, they caused only slight changes in TC levels. Hepatic cholesterol and triglyceride contents as well as mRNA levels of cholesterologenic and lipogenic enzymes suggest that leptin deficiency increased hepatic triglyceride production but did not change cholesterol production in ob/ob mice regardless of their LDLR genotype. These data provide evidence that the hypertriglyceridemia and hypercholesterolemia in the doubly mutant mice are caused by distinct mechanisms and point to the possibility that leptin might have some impact on plasma cholesterol metabolism, possibly through an LDLR-independent pathway. This model will be an excellent tool for future studies on the relationship between impaired fuel metabolism, increased plasma remnant lipoproteins, diabetes, and atherosclerosis.