Chen Yaxi, Zhao Lei, Li Qing, Wheeler David C, Varghese Zac, Moorhead John F, Powis Stephen H, Ruan Xiong Z
Centre for Lipid Research, Key Laboratory of Metabolism on Lipid and Glucose, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
John Moorhead Research Laboratory, Centre for Nephrology, University College London (UCL) Medical School, Royal Free Campus, University College London, London, UK.
Nephrol Dial Transplant. 2014 Oct;29(10):1864-78. doi: 10.1093/ndt/gfu203. Epub 2014 Jun 3.
Patients with chronic kidney disease (CKD) are unlikely to gain the same benefit from conventional doses of statins as do patients with cardiovascular disease alone. This study investigated whether inflammation accompanying CKD causes statin resistance.
Inflammatory stress was induced by adding cytokines and lipopolysaccharide (LPS) to human mesangial cells (HMCs) in vitro, and in vivo by subcutaneous casein injection in apolipoprotein E, scavenger receptors class A and CD36 triple knockout mice.
Inflammatory stress exacerbated cholesterol accumulation and was accompanied in vitro and in vivo by increased HMGCoA reductase (HMGCoA-R) mRNA and protein expression mediated via activation of the sterol regulatory element-binding protein cleavage-activating protein (SCAP)/sterol regulatory element-binding protein 2 pathway. Atorvastatin reduced HMGCoA-R enzymatic activity and intracellular cholesterol synthesis in vitro; however, inflammatory stress weakened these suppressive effects. Atorvastatin at concentrations of 15 µM inhibited HMGCoA-R activity by 50% (IC50) in HMCs, but the same concentration in the presence of interleukin (IL)-1β resulted in only 30% inhibition of HMGCoA-R activity in HMCs. Knocking down SCAP prevented statin resistance induced by IL-1β, and overexpression of SCAP-induced statin resistance even without inflammatory stress. In vivo, the amount of atorvastatin required to lower serum cholesterol and decrease kidney lipid accumulation rose from 2 to 10 mg/kg/day in the presence of inflammatory stress.
Inflammatory stress can disrupt HMGCoA-R-mediated cholesterol synthesis resulting in intracellular lipid accumulation and statin resistance.
慢性肾脏病（CKD）患者不太可能像单纯患有心血管疾病的患者那样从常规剂量的他汀类药物中获得相同的益处。本研究调查了CKD伴随的炎症是否会导致他汀类药物抵抗。
在体外，通过向人系膜细胞（HMCs）中添加细胞因子和脂多糖（LPS）诱导炎症应激；在体内，通过向载脂蛋白E、清道夫受体A类和CD36三联敲除小鼠皮下注射酪蛋白诱导炎症应激。
炎症应激加剧了胆固醇积累，在体外和体内均伴随着通过固醇调节元件结合蛋白裂解激活蛋白（SCAP）/固醇调节元件结合蛋白2途径的激活介导的HMGCoA还原酶（HMGCoA-R）mRNA和蛋白表达增加。阿托伐他汀在体外降低了HMGCoA-R酶活性和细胞内胆固醇合成；然而，炎症应激削弱了这些抑制作用。在HMCs中，15 μM浓度的阿托伐他汀可抑制HMGCoA-R活性达50%（IC50），但在存在白细胞介素（IL）-1β的情况下，相同浓度仅导致HMCs中HMGCoA-R活性被抑制30%。敲低SCAP可预防IL-1β诱导的他汀类药物抵抗，即使在没有炎症应激的情况下，SCAP的过表达也会诱导他汀类药物抵抗。在体内，在存在炎症应激的情况下，降低血清胆固醇和减少肾脏脂质积累所需的阿托伐他汀量从2 mg/kg/天增加到10 mg/kg/天。
炎症应激可破坏HMGCoA-R介导的胆固醇合成，导致细胞内脂质积累和他汀类药物抵抗。
