Submitted on May 4, 2007
Accepted on July 11, 2007
Inflammatory cytokines disrupt LDL receptor feedback regulation and cause statin resistance: a comparative study in human hepatic cells and mesangial cells
Yaxi Chen1, Xiong Z Ruan2*, Qiu Li1, Ailong Huang1, John F Moorhead3, Stephen H Powis3, and Zac Varghese3
1 Centre for Lipid Research, Key Laboratory of Molecular Biology on Infectious Disease, Chongqing Medical University, Chongqing, Chongqing, China
2 Centre for Nephrology, Royal Free and University College Medical School, London, United Kingdom; Centre for Lipid Research, Key Laboratory of Molecular Biology on Infectious Disease, Chongqing Medical University, Chongqing, Chongqing, China
3 Centre for Nephrology, Royal Free and University College Medical School, London, United Kingdom
* To whom correspondence should be addressed. E-mail: x.ruan{at}medsch.ucl.ac.uk.
LDL receptor (LDLr) is widely expressed in both liver and peripheral tissue. We aimed to clarify tissue specific regulation 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 for 50% inhibition of LDLr mRNA expression (IC50) in HepG2 was 75µg/ml, but only 30µg/ml in HMCs. The concentration of mevastatin, an HMGCoA reductase inhibitor, which achieved 200% up-regulation of LDLr (UC200) in HepG2 cells was 0.7µM, which is much lower than 2.8µM in HMCs. Inflammatory stress increased IC50 to 80µg/ml and 75µg/ml, UC200 to 2.8µM, and 4.2µM in HepG2 and HMCs, respectively. There was obvious SCAP accumulation in the Golgi in HepG2 cells but not in HMCs in the presence of high concentration of LDL. IL-1
further increased SCAP accumulation in HepG2 and HMCs in the presence of high concentration of LDL. These results indicate that LDLr in HepG2 cells has a relative resistant phenotype for down-regulation while LDLr in HMCs is very sensitive for down-regulation. 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.
