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

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Abstract
Previous studies have demonstrated that inflammatory cytokines such as interleukin-1β (IL-1β) 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-1β on the efflux of lipid from HMC was investigated. IL-1β 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 receptorα (LXRα) were examined. IL-1β (5 ng/ml) reduced PPARα, PPARγ, and LXRα mRNA expression. Activation of PPARγ with the agonist prostaglandin J2 (10 μM) and of PPARα with either bezafibrate (100 μM) or Wy14643 (100 μM) both increased LXRα and ABCA1 gene expression also and enhanced apoA1-mediated cholesterol efflux from lipid-loaded cells, even in the presence of IL-1β. A natural ligand of LXRα, 25-hydroxycholesterol (25-OHC), had similar effects; when used together with PPAR agonists, an additive effect was observed, indicating co-operation between PPAR and LXRα in regulating ABCA1 gene expression. This was supported by the observation that overexpression of either PPARα or PPARγ by transfection enhanced LXRα 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-LXRα-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

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