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Effect of cilostazol on hepatic low-density lipoprotein receptor-related protein 1 (LRP1) expression in vitro and in vivo model

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 Cilostazol 이 in vitro 와 in vivo model 의 간 low-density lipoprotein receptor-related protein (LRP1)의 발현에 주는 효과 
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Dept. of Medicine/석사
Cilostazol, a selective phosphodiesterase 3 (PDE3) inhibitor, is a vasodilating and anti-thrombotic agent. The mechanism whereby cilostazol reduces plasma triglyceride is not completely understood. Here we utilized in vitro (HepG2, Hep3B) and in vivo (C57BL/6) model to investigate the effect of cilostazol on a remnant lipoprotein receptor, low-density lipoprotein receptor-related protein 1 (LRP1), which has been reported to play an essential role in clearance of circulating triglyceride in the liver. Cilostazol increased both mRNA and protein expression of LRP1 in HepG2 and Hep3B cells. In addition, enhanced transcriptional activity of the LRP1 promoter containing a peroxisome proliferator reponse element (PPRE) was observed upon cilostazol treatment. Electrophoretic mobility shift assay (EMSA) confirmed that cilostazol activated peroxisome proliferator activated receptor-γ (PPAR-γ) binding to the PPRE of the LRP1 promoter. Cilostazol treatment enhanced the uptake of lipidated apoE3, and this effect was abolished when LRP1 was silenced by siRNA knockdown. A 10 week high-fat diet (60% kcal) induced hyperglycemia with high level of plasma triglycerides, and reduced hepatic LRP1 expression in C57BL/6 mice. Treatment with cilostazol for the same period of time, however, successfully prevented this down-regulation of LRP1 expression, and significantly reduced plasma triglycerides. Our results demonstrated that cilostazol enhances LRP1 expression in liver by activating PPARγ binding to PPRE in the LRP1 promoter. Increased hepatic LRP1 may be essential for the reduction of circulating triglyceride by cilostazol.
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