Davies John D, Carpenter Keri L H, Challis Iain R, Figg Nikki L, McNair Rosamund, Proudfoot Diane, Weissberg Peter L, Shanahan Catherine M
Department of Medicine, University of Cambridge, ACCI, Box 110, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 2QQ, United Kingdom.
J Biol Chem. 2005 Feb 4;280(5):3911-9. doi: 10.1074/jbc.M410075200. Epub 2004 Nov 16.
Lipid accumulation by vascular smooth muscle cells (VSMC) is a feature of atherosclerotic plaques. In this study we describe two mechanisms whereby human VSMC foam cell formation is driven by de novo synthesis of fatty acids leading to triacylglycerol accumulation in intracellular vacuoles, a process distinct from serum lipoprotein uptake. VSMC cultured in adipogenic differentiation medium accumulated lipids and were induced to express the adipocyte marker genes adipsin, adipocyte fatty acid-binding protein, C/EBPalpha, PPARgamma, and leptin. However, complete adipocyte differentiation was not observed as numerous genes present in mature adipocytes were not detected, and the phenotype was reversible. The rate of lipid accumulation was not affected by PPARgamma agonists, but screening for the effects of other nuclear receptor agonists showed that activation of the liver X receptors (LXR) dramatically promoted lipid accumulation in VSMC. Both LXRalpha and LXRbeta were present in VSMC, and their activation with TO901317 resulted in induction of the lipogenic genes fatty acid synthetase, sterol regulatory element binding protein (SREBP1c), and stearoyl-CoA desaturase. 27-Hydroxycholesterol, an abundant oxysterol synthesized by VSMC acted as an LXR antagonist and, therefore, may have a protective role in preventing foam cell formation. Immunohistochemistry showed that VSMC within atherosclerotic plaques express adipogenic and lipogenic markers, suggesting these pathways are present in vivo. Moreover, the development of an adipogenic phenotype in VSMC is consistent with their known phenotypic plasticity and may contribute to their dysfunction in atherosclerotic plaques and, thus, impinge on plaque growth and stability.
血管平滑肌细胞（VSMC）的脂质蓄积是动脉粥样硬化斑块的一个特征。在本研究中，我们描述了两种机制，即人类VSMC泡沫细胞的形成是由脂肪酸的从头合成驱动的，导致细胞内液泡中三酰甘油蓄积，这一过程不同于血清脂蛋白摄取。在成脂分化培养基中培养的VSMC蓄积脂质，并被诱导表达脂肪细胞标记基因，如脂肪酶、脂肪细胞脂肪酸结合蛋白、C/EBPα、PPARγ和瘦素。然而，未观察到完全的脂肪细胞分化，因为未检测到成熟脂肪细胞中存在的许多基因，且该表型是可逆的。脂质蓄积率不受PPARγ激动剂的影响，但对其他核受体激动剂作用的筛选表明，肝X受体（LXR）的激活显著促进了VSMC中的脂质蓄积。VSMC中同时存在LXRα和LXRβ，用TO901317激活它们会导致脂肪生成基因脂肪酸合成酶、固醇调节元件结合蛋白（SREBP1c）和硬脂酰辅酶A去饱和酶的诱导。27-羟基胆固醇是VSMC合成的一种丰富的氧化固醇，可作为LXR拮抗剂，因此可能在预防泡沫细胞形成中起保护作用。免疫组织化学显示，动脉粥样硬化斑块内的VSMC表达成脂和脂肪生成标记物，表明这些途径在体内存在。此外，VSMC中脂肪生成表型的发展与其已知的表型可塑性一致，可能导致其在动脉粥样硬化斑块中的功能障碍，从而影响斑块的生长和稳定性。
