Cardiovascular Research, Institute of Physiology, and Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.
PLoS One. 2010 Oct 22;5(10):e13539. doi: 10.1371/journal.pone.0013539.
Atherosclerosis is a chronic inflammatory disease that evolves from the interaction of activated endothelial cells, macrophages, lymphocytes and modified lipoproteins (LDLs). In the last years many molecules with crucial metabolic functions have been shown to prevent important steps in the progression of atherogenesis, including peroxisome proliferator activated receptors (PPARs) and the class III histone deacetylase (HDAC) SIRT1. The PPARγ coactivator 1 alpha (Ppargc1a or PGC-1α) was identified as an important transcriptional cofactor of PPARγ and is activated by SIRT1. The aim of this study was to analyze total PGC-1α deficiency in an atherosclerotic mouse model.
METHODOLOGY/PRINCIPAL FINDINGS: To investigate if total PGC-1α deficiency affects atherosclerosis, we compared ApoE(-/-) PGC-1α(-/-) and ApoE(-/-) PGC-1α(+/+) mice kept on a high cholesterol diet. Despite having more macrophages and a higher ICAM-1 expression in plaques, ApoE(-/-) PGC-1α(-/-) did not display more or larger atherosclerotic plaques than their ApoE(-/-) PGC-1α(+/+) littermates. In line with the previously published phenotype of PGC-1α(-/-) mice, ApoE(-/-) PGC-1α(-/-) mice had marked reduced body, liver and epididymal white adipose tissue (WAT) weight. VLDL/LDL-cholesterol and triglyceride contents were also reduced. Aortic expression of PPARα and PPARγ, two crucial regulators for adipocyte differentiation and glucose and lipid metabolism, as well as the expression of some PPAR target genes was significantly reduced in ApoE(-/-) PGC-1α(-/-) mice. Importantly, the epididymal WAT and aortic expression of IL-18 and IL-18 plasma levels, a pro-atherosclerotic cytokine, was markedly reduced in ApoE(-/-) PGC-1α(-/-) mice.
CONCLUSIONS/SIGNIFICANCE: ApoE(-/-) PGC-1α(-/-) mice, similar as PGC-1α(-/-) mice exhibit markedly reduced total body and visceral fat weight. Since inflammation of visceral fat is a crucial trigger of atherogenesis, decreased visceral fat in PGC-1α-deficient mice may explain why these mice do not develop enhanced atherosclerosis.
动脉粥样硬化是一种慢性炎症性疾病，源于激活的内皮细胞、巨噬细胞、淋巴细胞和修饰的脂蛋白（LDL）之间的相互作用。近年来，许多具有关键代谢功能的分子被证明可以阻止动脉粥样硬化发生过程中的重要步骤，包括过氧化物酶体增殖物激活受体（PPARs）和 III 类组蛋白去乙酰化酶（HDAC）SIRT1。过氧化物酶体增殖物激活受体γ共激活因子 1α（Ppargc1a 或 PGC-1α）被鉴定为 PPARγ的重要转录共激活因子，并且由 SIRT1 激活。本研究的目的是分析动脉粥样硬化小鼠模型中总 PGC-1α 缺乏的情况。
方法/主要发现：为了研究总 PGC-1α 缺乏是否会影响动脉粥样硬化，我们比较了高脂饮食下的 ApoE（-/-）PGC-1α（-/-）和 ApoE（-/-）PGC-1α（+/+）小鼠。尽管斑块中巨噬细胞更多，ICAM-1 表达更高，但 ApoE（-/-）PGC-1α（-/-）小鼠的动脉粥样硬化斑块并不比其 ApoE（-/-）PGC-1α（+/+）同窝小鼠更多或更大。与先前发表的 PGC-1α（-/-）小鼠表型一致，ApoE（-/-）PGC-1α（-/-）小鼠的体重、肝脏和附睾白色脂肪组织（WAT）重量明显减少。VLDL/LDL-胆固醇和甘油三酯含量也降低。ApoE（-/-）PGC-1α（-/-）小鼠的主动脉中 PPARα 和 PPARγ的表达，这两种对脂肪细胞分化和葡萄糖及脂质代谢至关重要的调节因子，以及一些 PPAR 靶基因的表达也明显降低。重要的是，ApoE（-/-）PGC-1α（-/-）小鼠的附睾白色脂肪组织和主动脉中白细胞介素 18（IL-18）和白细胞介素 18（IL-18）的表达及其血浆水平，一种促动脉粥样硬化细胞因子，明显降低。
结论/意义：ApoE（-/-）PGC-1α（-/-）小鼠与 PGC-1α（-/-）小鼠一样，总体重和内脏脂肪重量明显减轻。由于内脏脂肪的炎症是动脉粥样硬化发生的关键触发因素，PGC-1α 缺乏小鼠内脏脂肪减少可能解释了为什么这些小鼠不会发生增强的动脉粥样硬化。
