Ruan X Z, Moorhead J F, Fernando R, Wheeler D C, Powis S H, Varghese Z
Centre for Nephrology, Royal Free and University College Medical School, University College London, Royal Free Campus, Rowland Hill Street, London NW3 2PF, UK.
Biochem Soc Trans. 2004 Feb;32(Pt 1):88-91. doi: 10.1042/bst0320088.
Inflammation and dyslipidaemia both play important roles in the development of glomerular atherosclerosis in renal diseases. We have demonstrated that inflammatory mediators induced Scr (scavenger receptor) expression and the formation of foam cells, and that AP-1 (activator protein 1)/ets were necessary transcriptional factors for Scr induction in HMCs (human kidney mesangial cells). Most cells are protected from excessive native LDL (low-density lipoprotein) accumulation by tight feedback regulation of the LDLr (LDL receptor). However, we observed that HMCs formed foam cells via the LDLr pathway when incubated with IL-1beta (interleukin-1beta; 5 ng/ml) and unmodified LDL (200 microg/ml), suggesting that inflammatory mediators may disrupt the cholesterol-mediated feedback regulation. This feedback involves cholesterol-mediated down-regulation of LDLr controlled by SCAP [SREBP (sterol responsive element-binding protein) cleavage-activating protein]. We have also demonstrated that both tumour necrosis factor alpha and IL-1beta increased nuclear SREBP-1 levels by increasing SCAP mRNA expression, even in the presence of a high concentration of LDL. Since intracellular lipid content is governed by both influx and efflux mechanisms, we set out to examine the impact of inflammatory cytokines on cholesterol efflux, a process mediated by the protein ABCA1 (ATP binding cassette A1). IL-1beta inhibited [(3)H]cholesterol efflux from HMCs by inhibition of the peroxisome-proliferator-activated receptor/LXR (liver X receptor)/ABCA1 pathway. Taken together, our results suggest that inflammatory mediators increase lipid accumulation in HMCs not only by promoting increased lipoprotein uptake by Scr and LDLr, but also by inhibiting ABCA1-mediated cholesterol efflux to high-density lipoprotein.
炎症和血脂异常在肾脏疾病中肾小球动脉粥样硬化的发展过程中均发挥着重要作用。我们已经证明，炎症介质可诱导清道夫受体（Scr）表达以及泡沫细胞的形成，并且激活蛋白1（AP-1）/ets是人类肾小球系膜细胞（HMCs）中Scr诱导所必需的转录因子。大多数细胞通过低密度脂蛋白受体（LDLr）的严格反馈调节来防止过量天然低密度脂蛋白（LDL）的蓄积。然而，我们观察到，当HMCs与白细胞介素-1β（IL-1β；5纳克/毫升）和未修饰的LDL（200微克/毫升）一起孵育时，它们会通过LDLr途径形成泡沫细胞，这表明炎症介质可能会破坏胆固醇介导的反馈调节。这种反馈涉及由固醇调节元件结合蛋白（SREBP）裂解激活蛋白（SCAP）控制的胆固醇介导的LDLr下调。我们还证明，即使在高浓度LDL存在的情况下，肿瘤坏死因子α和IL-1β均通过增加SCAP mRNA表达来提高核SREBP-1水平。由于细胞内脂质含量受流入和流出机制的共同控制，我们着手研究炎症细胞因子对胆固醇流出的影响，这一过程由ATP结合盒A1（ABCA1）蛋白介导。IL-1β通过抑制过氧化物酶体增殖物激活受体/肝X受体（LXR）/ABCA1途径来抑制HMCs中[³H]胆固醇的流出。综上所述，我们的结果表明，炎症介质增加HMCs中脂质蓄积不仅是通过促进Scr和LDLr介导的脂蛋白摄取增加，还通过抑制ABCA1介导的胆固醇向高密度脂蛋白的流出。
