Antagonistic effects of oxidized low density lipoprotein and alpha-tocopherol on CD36 scavenger receptor expression in monocytes: involvement of protein kinase B and peroxisome proliferator-activated receptor-gamma.
Vitamin E deficiency increases expression of the CD36 scavenger receptor, suggesting specific molecular mechanisms and signaling pathways modulated by alpha-tocopherol. We show here that alpha-tocopherol down-regulated CD36 expression (mRNA and protein) in oxidized low density lipoprotein (oxLDL)-stimulated THP-1 monocytes, but not in unstimulated cells. Furthermore, alpha-tocopherol treatment of monocytes led to reduction of fluorescent oxLDL-3,3'-dioctadecyloxacarbocyanine perchlorate binding and uptake. Protein kinase C (PKC) appears not to be involved because neither activation of PKC by phorbol 12-myristate 13-acetate nor inhibition by PKC412 was affected by alpha-tocopherol. However, alpha-tocopherol could partially prevent CD36 induction after stimulation with a specific agonist of peroxisome proliferator-activated receptor-gamma (PPARgamma; troglitazone), indicating that this pathway is susceptible to alpha-tocopherol action. Phosphorylation of protein kinase B (PKB) at Ser473 was increased by oxLDL, and alpha-tocopherol could prevent this event. Expression of PKB stimulated the CD36 promoter as well as a PPARgamma element-driven reporter gene, whereas an inactive PKB mutant had no effect. Moreover, coexpression of PPARgamma and PKB led to additive induction of CD36 expression. Altogether, our results support the existence of PKB/PPARgamma signaling pathways that mediate CD36 expression in response to oxLDL. The activation of CD36 expression by PKB suggests that both lipid biosynthesis and fatty acid uptake are stimulated by PKB.
Munteanu
Adelina
A
Institute of Biochemistry and Molecular Medicine, University of Bern, Bühlstrasse 28, 3012 Bern, Switzerland.
Taddei
Michele
M
Tamburini
Ilaria
I
Bergamini
Ettore
E
Azzi
Angelo
A
Zingg
Jean-Marc
JM
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D018955:CD36 Antigens / Q000096:biosynthesis* / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D006801:Humans; D008077:Lipoproteins, LDL / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D047495:PPAR gamma / Q000502:physiology*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014811:Vitamin E Deficiency / Q000378:metabolism / Q000503:physiopathology; D024502:alpha-Tocopherol / Q000737:chemistry / Q000494:pharmacology*
D018955:CD36 Antigens; D008077:Lipoproteins, LDL; D016328:NF-kappa B; D047495:PPAR gamma; D012333:RNA, Messenger; C099252:oxidized low density lipoprotein; D051057:Proto-Oncogene Proteins c-akt; D024502:alpha-Tocopherol