- 作者：Hyung Jun Kim ; Jae Hoon Moon ; Hyun Min Kim ; Mi Ra Yun ; Byung Hun Jeon ; ByungWan Lee ; Eun Seok Kang ; Hyun Chul Lee ; Bong Soo Cha
- 关键词：PDE3 ; phosphodiesterase 3 ; HDL ; high-density lipoprotein ; TG ; triglyceride ; VLDL ; very low-density lipoproteins ; LRP1 ; low-density lipoprotein receptor-related protein 1 ; LDL ; low-density lipoprotein ; apoE ; apolipoprotein E ; CR ; chylomicron remnants ; HSPG ; heparan sulfate proteoglycans ; PPAR-纬 ; peroxisome proliferator activated receptor-纬 ; PPRE ; peroxisome proliferator response element ; MEM ; minimum essential medium ; DMSO ; dimethyl sulfoxide ; IPGTT ; i.p. glucose tolerance test ; H&E ; hematoxyli
- 刊名：Metabolism
- 出版年：January, 2014
- 年：2014
- 卷：63
- 期：1
- 页码：112-119
- 全文大小：1431 K
Objectives
Cilostazol, a selective phosphodiesterase 3 (PDE3) inhibitor, is a vasodilator and an anti-thrombotic agent. The mechanism whereby cilostazol reduces plasma triglyceride is not completely understood. Here we investigated 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.Materials/Methods
Total cellular expression, and functional and transcriptional regulation of LRP1 were analyzed in human hepatocarcinoma cell lines incubated with cilostazol. Also, C57BL/6 mice were subjected to high-fat diet (60% kcal) and cilostazol (30 mg/kg) treatment for 10 weeks.
Results
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 response element (PPRE) was observed after cilostazol exposure. Cilostazol treatment enhanced the uptake of lipidated apoE3, and this effect was abolished when LRP1 was silenced by siRNA knockdown. High-fat diet induced hyperglycemia with high level of plasma triglycerides, and reduced hepatic LRP1 expression in mice. Treatment with cilostazol for the same period of time, however, successfully prevented this down-regulation of LRP1 expression and reduced plasma triglycerides.
Conclusion
Taken together, our results demonstrated that cilostazol enhances LRP1 expression in liver by activating PPAR纬 through the PPRE in the LRP1 promoter. Increased hepatic LRP1 may be essential for the reduction of circulating triglycerides brought about by cilostazol.