Haraguchi Go, Kobayashi Yasushi, Brown Matthew L, Tanaka Akira, Isobe Mitsuaki, Gianturco Sandra H, Bradley William A
Tokyo Medical and Dental University, Department of Cardiovascular Medicine, Tokyo 113-8519, Japan.
J Lipid Res. 2003 Jun;44(6):1224-31. doi: 10.1194/jlr.M300077-JLR200. Epub 2003 Apr 16.
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.
某些富含甘油三酯的脂蛋白（TRL），特别是乳糜微粒、血脂异常的极低密度脂蛋白（VLDL）及其残粒，具有致动脉粥样硬化作用，并且在体外可通过载脂蛋白B - 48受体（apoB - 48R）诱导单核细胞 - 巨噬细胞泡沫细胞形成。经免疫组织化学测定，人类动脉粥样硬化病变中的泡沫细胞表达apoB - 48R，这表明它可能在体内巨噬细胞向泡沫细胞的转化过程中发挥作用。尽管先前的研究表明细胞固醇水平和分化状态不影响apoB - 48R的表达，但单核细胞 - 巨噬细胞中apoB - 48R的调控机制尚未完全明确。由于过氧化物酶体增殖物激活受体（PPAR）调节细胞脂质代谢的某些方面，并且可能通过上调肝脏X激活受体α和ATP结合盒转运体A1对动脉粥样硬化形成具有保护作用，因此我们研究了PPAR配体对人单核细胞 - 巨噬细胞中apoB - 48R的调控作用。通过实时PCR、Northern杂交、Western印迹以及功能性细胞脂质积累测定，我们发现PPARα和PPARγ激活剂可显著抑制人THP - 1细胞和血源性单核细胞 - 巨噬细胞中apoB - 48R mRNA的表达。此外，PPAR激活剂可抑制apoB - 48R蛋白的表达，并且值得注意的是，在体外可抑制THP - 1单核细胞中apoB - 48R介导的TRL脂质积累。如果PPAR激活剂在体内也抑制apoB - 48R途径，那么apoB - 48R介导的单核细胞 - 巨噬细胞脂质积累减少可能是PPAR配体作用的另一种抗动脉粥样硬化效应。
