ROLES OF SCAP (STEROL REGULATORY ELEMENT–BINDING PROTEIN CLEAVAGE-ACTIVATING PROTEIN) IN THE MECHANISM FOR MESANGIAL FOAM-CELL FORMATION UNDER INFLAMMATORY STRESS
INTRODUCTION: Our previous studies have demonstrated that lipid abnormalities play a significant role in glomerulosclerosis. Inflammatory cytokines promote lipid accumulation in human mesangial cells (HMCLs) by disrupting low-density lipoprotein receptor (LDLr) feedback regulation. The sterol regulatory element–binding protein (SREBP) cleavage-activating protein (SCAP) carries SREBP from endoplasmic reticulum (ER) to Golgi, where it is known to cleave SREBP, thereby enhancing LDLr gene expression and cholesterol uptake when cells need cholesterol.
OBJECTIVE: We aimed to investigate whether inflammatory mediators interfere with SCAP translocation and its biological consequence.
METHODS: HMCLs were used in all experiments. Total cellular RNA was isolated from these cells for detecting LDLr, SREBP-2, and SCAP messenger RNA levels with real-time quantitative polymerase chain reaction. LDLr protein expression was measured by Western blot. Translocation of the SCAP-SREBP complex from the ER to Golgi was investigated by confocal microscopy.
RESULTS: In the absence of exposure to interleukin 1β, a high concentration of LDL retained SCAP in the ER, a low LDLr promoter activity, messenger RNA synthesis, and protein expression were found, respectively. However, exposure to interleukin 1β caused overexpression of SCAP and enhanced its translocation from the ER to Golgi. This disrupted normal feedback regulation and resulted in inappropriately increased LDL uptake with transformation of HMCLs into foam cells. Overexpression of SCAP in HMCLs resulted in an increased translocation of SCAP from the ER to Golgi, and high concentrations of LDL were unable to suppress SREBP-2 and LDLr gene expression.
CONCLUSIONS: These data suggest that inflammatory mediators promote abnormal translocation of SCAP from the ER to Golgi and play an important role in lipid accumulation in HMCLs.
Submitted by Qiu Li
- Copyright © 2008 by the American Academy of Pediatrics