2007 JASN IMPACT FACTOR 7.111	HOME   AUTHOR INFO   EDITORIAL BOARD   SUBSCRIBE   FEEDBACK   ALERTS   HELP
advanced	CURRENT ISSUE	ARCHIVES	JASN Express	ONLINE SUBMISSION

This Article Full Text Full Text (PDF) 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 PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ruan, X. Z. Articles by Varghese, Z. Search for Related Content PubMed PubMed Citation Articles by Ruan, X. Z. Articles by Varghese, Z.

PPAR Agonists Protect Mesangial Cells from Interleukin 1-Induced Intracellular Lipid Accumulation by Activating the ABCA1 Cholesterol Efflux Pathway

Centre for Nephrology, Royal Free and University College Medical School, London, United Kingdom.

Correspondence to Dr. Zac Varghese, Centre for Nephrology, Royal Free and University College Medical School, University College London, Royal Free Campus, Rowland Hill Street, London NW3 2PF, UK. Phone: 44-20-7830-2190; Fax: 44-20-7830-2125;

ABSTRACT. Previous studies have demonstrated that inflammatory cytokines such as interleukin-1 (IL-1) promote lipid accumulation in human mesangial cells (HMC) by dysregulating the expression of lipoprotein receptors. Intracellular lipid accumulation is governed by both influx and efflux; therefore, the effect of IL-1 on the efflux of lipid from HMC was investigated. IL-1 was shown to inhibit ³H-cholesterol efflux from HMC and increase total intracellular cholesterol concentration, probably as a result of reduced expression of the adenosine triphosphate (ATP) binding cassette A1 (ABCA1), a transporter protein involved in apolipoprotein-A1 (apo-A1)–mediated lipid efflux. To ascertain the molecular mechanisms involved, expression of peroxisome proliferator-activated receptors (PPAR) and liver X receptor (LXR) were examined. IL-1 (5 ng/ml) reduced PPAR, PPAR, and LXR mRNA expression. Activation of PPAR with the agonist prostaglandin J2 (10 µM) and of PPAR with either bezafibrate (100 µM) or Wy14643 (100 µM) both increased LXR and ABCA1 gene expression also and enhanced apoA1-mediated cholesterol efflux from lipid-loaded cells, even in the presence of IL-1. A natural ligand of LXR, 25-hydroxycholesterol (25-OHC), had similar effects; when used together with PPAR agonists, an additive effect was observed, indicating co-operation between PPAR and LXR in regulating ABCA1 gene expression. This was supported by the observation that overexpression of either PPAR or PPAR by transfection enhanced LXR and ABCA1 gene induction by PPAR agonists. Taken together with previous data, it appears that, in addition to increasing lipid uptake, inflammatory cytokines promote intracellular lipid accumulation by inhibiting cholesterol efflux through the PPAR-LXR-ABCA1 pathway. These results suggest potential mechanisms whereby inflammation may exacerbate lipid-mediated cellular injury in the glomerulus and in other tissues and indicate that PPAR agonists may have a protective effect. E-mail: zvarghese@rfc.ucl.ac.uk

This article has been cited by other articles:

				X. Ruan, F. Zheng, and Y. Guan PPARs and the kidney in metabolic syndrome Am J Physiol Renal Physiol, May 1, 2008; 294(5): F1032 - F1047. [Abstract] [Full Text] [PDF]

				Y. Chen, X. Z. Ruan, Q. Li, A. Huang, J. F. Moorhead, S. H. Powis, and Z. Varghese Inflammatory cytokines disrupt LDL-receptor feedback regulation and cause statin resistance: a comparative study in human hepatic cells and mesangial cells Am J Physiol Renal Physiol, September 1, 2007; 293(3): F680 - F687. [Abstract] [Full Text] [PDF]

				K. L. Ma, X. Z. Ruan, S. H. Powis, J. F. Moorhead, and Z. Varghese Anti-atherosclerotic effects of sirolimus on human vascular smooth muscle cells Am J Physiol Heart Circ Physiol, June 1, 2007; 292(6): H2721 - H2728. [Abstract] [Full Text] [PDF]

				C. Berruyer, L. Pouyet, V. Millet, F. M. Martin, A. LeGoffic, A. Canonici, S. Garcia, C. Bagnis, P. Naquet, and F. Galland Vanin-1 licenses inflammatory mediator production by gut epithelial cells and controls colitis by antagonizing peroxisome proliferator-activated receptor {gamma} activity J. Exp. Med., December 25, 2006; 203(13): 2817 - 2827. [Abstract] [Full Text] [PDF]

				Y. Zhang, X. Zhang, L. Chen, J. Wu, D. Su, W. J. Lu, M.-T. Hwang, G. Yang, S. Li, M. Wei, et al. Liver X receptor agonist TO-901317 upregulates SCD1 expression in renal proximal straight tubule Am J Physiol Renal Physiol, May 1, 2006; 290(5): F1065 - F1073. [Abstract] [Full Text] [PDF]

				P. M. Hall Prevention of Progression in Diabetic Nephropathy Diabetes Spectr, January 1, 2006; 19(1): 18 - 24. [Abstract] [Full Text] [PDF]

				A. K. Berfield, A. Chait, J. F. Oram, R. A. Zager, A. C. Johnson, and C. K. Abrass IGF-1 induces rat glomerular mesangial cells to accumulate triglyceride Am J Physiol Renal Physiol, January 1, 2006; 290(1): F138 - F147. [Abstract] [Full Text] [PDF]

				S Soumian, R Gibbs, A Davies, and C Albrecht mRNA expression of genes involved in lipid efflux and matrix degradation in occlusive and ectatic atherosclerotic disease J. Clin. Pathol., December 1, 2005; 58(12): 1255 - 1260. [Abstract] [Full Text] [PDF]

				M. Xia, M. Hou, H. Zhu, J. Ma, Z. Tang, Q. Wang, Y. Li, D. Chi, X. Yu, T. Zhao, et al. Anthocyanins Induce Cholesterol Efflux from Mouse Peritoneal Macrophages: THE ROLE OF THE PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR {gamma}-LIVER X RECEPTOR {alpha}-ABCA1 PATHWAY J. Biol. Chem., November 4, 2005; 280(44): 36792 - 36801. [Abstract] [Full Text] [PDF]

				Z. Varghese, R. Fernando, J. F. Moorhead, S. H. Powis, and X. Z. Ruan Effects of sirolimus on mesangial cell cholesterol homeostasis: a novel mechanism for its action against lipid-mediated injury in renal allografts Am J Physiol Renal Physiol, July 1, 2005; 289(1): F43 - F48. [Abstract] [Full Text] [PDF]

				S Soumian, C Albrecht, A. Davies, and R. Gibbs ABCA1 and atherosclerosis Vascular Medicine, May 1, 2005; 10(2): 109 - 119. [Abstract] [PDF]

				Y. Guan Peroxisome Proliferator-Activated Receptor Family and Its Relationship to Renal Complications of the Metabolic Syndrome J. Am. Soc. Nephrol., November 1, 2004; 15(11): 2801 - 2815. [Abstract] [Full Text] [PDF]

				J. Wu, Y. Zhang, N. Wang, L. Davis, G. Yang, X. Wang, Y. Zhu, M. D. Breyer, and Y. Guan Liver X receptor-{alpha} mediates cholesterol efflux in glomerular mesangial cells Am J Physiol Renal Physiol, November 1, 2004; 287(5): F886 - F895. [Abstract] [Full Text] [PDF]

				P. K. Chatterjee, N. S.A Patel, S. Cuzzocrea, P. A.J Brown, K. N Stewart, H. Mota-Filipe, D. Britti, W. Eberhardt, J. Pfeilschifter, and C. Thiemermann The cyclopentenone prostaglandin 15-deoxy-{Delta}12,14-prostaglandin J2 ameliorates ischemic acute renal failure Cardiovasc Res, February 15, 2004; 61(3): 630 - 643. [Abstract] [Full Text] [PDF]

Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673