PPAR agonists protect mesangial cells from interleukin 1beta-induced intracellular lipid accumulation by activating the ABCA1 cholesterol efflux pathway.
Previous studies have demonstrated that inflammatory cytokines such as interleukin-1beta (IL-1beta) 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-1beta on the efflux of lipid from HMC was investigated. IL-1beta was shown to inhibit (3)H-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 receptoralpha (LXRalpha) were examined. IL-1beta (5 ng/ml) reduced PPARalpha, PPARgamma, and LXRalpha mRNA expression. Activation of PPARgamma with the agonist prostaglandin J2 (10 micro M) and of PPARalpha with either bezafibrate (100 micro M) or Wy14643 (100 micro M) both increased LXRalpha and ABCA1 gene expression also and enhanced apoA1-mediated cholesterol efflux from lipid-loaded cells, even in the presence of IL-1beta. A natural ligand of LXRalpha, 25-hydroxycholesterol (25-OHC), had similar effects; when used together with PPAR agonists, an additive effect was observed, indicating co-operation between PPAR and LXRalpha in regulating ABCA1 gene expression. This was supported by the observation that overexpression of either PPARalpha or PPARgamma by transfection enhanced LXRalpha 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-LXRalpha-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.
Ruan
Xiong Z
XZ
Centre for Nephrology, Royal Free and University College Medical School, London, United Kingdom.
Moorhead
John F
JF
Fernando
Ray
R
Wheeler
David C
DC
Powis
Stephen H
SH
Varghese
Zac
Z
D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000924:Anticholesteremic Agents / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D001629:Bezafibrate / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects; D002461:Cell Line, Transformed; D002784:Cholesterol / Q000378:metabolism*; D004268:DNA-Binding Proteins; D005920:Glomerular Mesangium / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D006888:Hydroxycholesterols / Q000494:pharmacology; D000960:Hypolipidemic Agents / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology*; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000235:genetics; D014157:Transcription Factors / Q000819:agonists* / Q000235:genetics
C473801:ABCA12 protein, human; D018528:ATP-Binding Cassette Transporters; D000924:Anticholesteremic Agents; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D006888:Hydroxycholesterols; D000960:Hypolipidemic Agents; D007375:Interleukin-1; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; D057093:Orphan Nuclear Receptors; D011743:Pyrimidines; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; C037112:9-deoxy-delta-9-prostaglandin D2; C007997:25-hydroxycholesterol; C006253:pirinixic acid; D002784:Cholesterol; D015230:Prostaglandin D2; D001629:Bezafibrate