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首页> 外文期刊>American Journal of Physiology >Inflammatory cytokines disrupt LDL-receptor feedback regulation and cause statin resistance: a comparative study in human hepatic cells and mesangial cells.
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Inflammatory cytokines disrupt LDL-receptor feedback regulation and cause statin resistance: a comparative study in human hepatic cells and mesangial cells.

机译：炎性细胞因子破坏LDL受体反馈调节并引起他汀类药物耐药：在人类肝细胞和系膜细胞中的比较研究。

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LDL receptor (LDLr) is widely expressed in both liver and peripheral tissue. We aimed to clarify tissue-specific regulation of LDLr in hepatic cell line (HepG2) cells and human kidney mesangial cells (HMCs) under physiological and inflammatory conditions. We have demonstrated that the concentration of LDL required for 50% inhibition of LDLr mRNA expression (IC50) in HepG2 was 75 microg/ml, but only 30 microg/ml in HMCs. The concentration of mevastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, which achieved 200% upregulation of LDLr (UC200) in HepG2 cells, was 0.7 microM, which is much lower than 2.8 microM in HMCs. Inflammatory stress increased IC50 to 80 and 75 microg/ml of LDL, UC(200) to 2.8 microM, and 4.2 microM of mevastatin in HepG2 and HMCs. There was obvious sterol-regulatory element binding protein cleavage-activating protein accumulation in the Golgi in HepG2 cells, but not in HMCs in the presence of high concentration of LDL. IL-1beta further increased sterol-regulatoryelement binding protein cleavage-activating protein accumulation in HepG2 and HMCs in the presence of high concentration of LDL. These results indicate that LDLr in HepG2 cells have a relative resistant phenotype for downregulation, while LDLr in HMCs is very sensitive for downregulation. Inflammatory cytokine disrupts LDLr negative feedback regulation induced by intracellular cholesterol in both cell types, to a greater degree in HMCs, which could be one reason why HMCs are more prone to become foam cells under inflammatory stress. Inflammation also causes statin resistance; therefore, a high concentration of statin may be required to achieve the same biological effect.
机译：LDL受体（LDLr）在肝脏和周围组织中广泛表达。我们旨在阐明生理和炎性条件下肝细胞系（HepG2）细胞和人肾小球膜细胞（HMCs）中LDLr的组织特异性调节。我们已经证明，HepG2中50％抑制LDLr mRNA表达（IC50）所需的LDL浓度为75微克/毫升，而在HMC中仅为30微克/毫升。在HepG2细胞中实现LDLr（UC200）200％上调的美伐他汀（一种3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂）的浓度为0.7 microM，远低于HMC中的2.8 microM。炎性应激使HepG2和HMC中的美伐他汀的IC50升高至LDL的IC50达到80和75 microg / ml，UC（200）升高至2.8 microM和4.2 microM。在高浓度LDL存在下，HepG2细胞中高尔基体中有明显的固醇调节元件结合蛋白裂解激活蛋白蓄积，而在HMC中则没有。在高浓度的LDL存在下，IL-1beta进一步增加了HepG2和HMC中固醇调节因子结合蛋白的裂解活化蛋白的积累。这些结果表明，HepG2细胞中的LDLr对下调具有相对抗性表型，而HMC中的LDLr对下调非常敏感。在HMC中，炎性细胞因子在更大程度上破坏了两种细胞类型中由细胞内胆固醇诱导的LDLr负反馈调节，这可能是HMC在炎性应激下更倾向于成为泡沫细胞的原因之一。炎症也会引起他汀类药物耐药。因此，可能需要高浓度的他汀类药物才能达到相同的生物学效果。

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