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This Article Full Text Full Text (PDF) All Versions of this Article: 293/3/F680    most recent 00209.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via ISI Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Chen, Y. Articles by Varghese, Z. Search for Related Content PubMed PubMed Citation Articles by Chen, Y. Articles by Varghese, Z.

Inflammatory cytokines disrupt LDL-receptor feedback regulation and cause statin resistance: a comparative study in human hepatic cells and mesangial cells

¹Centre for Lipid Research, Key Laboratory of Molecular Biology on Infectious Diseases, Chongqing Medical University, Peoples Republic of China; and ²Centre for Nephrology, Royal Free and University College Medical School, London, United Kingdom

Submitted 4 May 2007 ; accepted in final form 11 July 2007

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 µg/ml, but only 30 µg/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 µM, which is much lower than 2.8 µM in HMCs. Inflammatory stress increased IC₅₀ to 80 and 75 µg/ml of LDL, UC₂₀₀ to 2.8 µM, and 4.2 µM 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-1 further increased sterol-regulatory element 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.

inflammation; kidney mesangial cells; hepatic cells