PPAR(alpha) and PPAR(gamma) activators suppress the monocyte-macrophage apoB-48 receptor.
Certain triglyceride-rich lipoproteins (TRLs), specifically chylomicrons, dyslipemic VLDLs, and their remnants, are atherogenic and can induce monocyte-macrophage foam cell formation in vitro via the apolipoprotein B-48 receptor (apoB-48R). Human atherosclerotic lesion foam cells express the apoB-48R, as determined immunohistochemically, suggesting it can play a role in the conversion of macrophages into foam cells in vivo. The regulation of the apoB-48R in monocyte-macrophages is not fully understood, albeit previous studies indicated that cellular sterol levels and state of differentiation do not affect apoB-48R expression. Since peroxisome proliferator-activated receptors (PPARs) regulate some aspects of cellular lipid metabolism and may be protective in atherogenesis by up-regulation of liver X-activated receptor alpha and ATP-binding cassette transporter A1, we examined the regulation of apoB-48R by PPAR ligands in human monocyte-macrophages. Using real-time PCR, Northern, Western, and functional cellular lipid accumulation assays, we show that PPARalpha and PPARgamma activators significantly suppress the expression of apoB-48R mRNA in human THP-1 and blood-borne monocyte-macrophages. Moreover, PPAR activators inhibit the expression of the apoB-48R protein and, notably, the apoB-48R-mediated lipid accumulation of TRL by THP-1 monocytes in vitro. If PPAR activators also suppress the apoB-48R pathway in vivo, diminished apoB-48R-mediated monocyte-macrophage lipid accumulation may be yet another antiatherogenic effect of the action of PPAR ligands.
Haraguchi
Go
G
Tokyo Medical and Dental University, Department of Cardiovascular Medicine, Tokyo 113-8519, Japan.
Kobayashi
Yasushi
Y
Brown
Matthew L
ML
Tanaka
Akira
A
Isobe
Mitsuaki
M
Gianturco
Sandra H
SH
Bradley
William A
WA
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D053283:Apolipoprotein B-48; D001055:Apolipoproteins B / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D001161:Arteriosclerosis / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D018955:CD36 Antigens / Q000378:metabolism; D002460:Cell Line; D015536:Down-Regulation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology; D008024:Ligands; D050356:Lipid Metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000378:metabolism*; D014157:Transcription Factors / Q000819:agonists / Q000378:metabolism*
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D053283:Apolipoprotein B-48; D001055:Apolipoproteins B; D018955:CD36 Antigens; D000960:Hypolipidemic Agents; D008024:Ligands; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors