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The hypolipidemic effect of cilostazol can be mediated by regulation of hepatic low-density lipoprotein receptor-related protein 1 (LRP 1) expression

 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 
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Animals ; Apolipoprotein E3/metabolism ; Blotting, Western ; Carcinoma, Hepatocellular/metabolism ; Cell Line, Tumor ; Diet, High-Fat ; Down-Regulation ; Gene Expression Regulation, Neoplastic ; Gene Silencing ; Hep G2 Cells ; Humans ; Hypolipidemic Agents/pharmacology* ; Liver/metabolism* ; Liver Neoplasms/metabolism ; Low Density Lipoprotein Receptor-Related Protein-1/drug effects ; Low Density Lipoprotein Receptor-Related Protein-1/genetics ; Low Density Lipoprotein Receptor-Related Protein-1/metabolism* ; Mice ; Mice, Inbred C57BL ; Real-Time Polymerase Chain Reaction ; Tetrazoles/pharmacology* ; Transcription, Genetic ; Triglycerides/blood*
1,2-dimyristoyl-sn-glycero-3-phosphocholin ; 2-chloro-5-nitrobenzanilide ; 3,3′-Diaminobenzidine ; 4′,6-diamidino-2-phenylindole ; Atherosclerosis ; CR ; DAB ; DAPI ; DMPC ; DMSO ; DNase ; Dyslipidemia ; GW9662 ; Glut 4 ; H&E ; HDL ; HSPG ; HUVEC ; IPGTT ; LDL ; LPL ; LRP1 ; MEM ; PCR ; PDE3 ; PPAR-γ ; PPARγ ; PPRE ; Polymerase chain reaction ; RNase ; RT ; RT-PCR ; Reverse transcriptase ; STZ ; TG ; VLDL ; apoE ; apolipoprotein E ; chylomicron remnants ; dNTP ; deoxyriboNTP ; deoxyribonuclease ; dimethyl sulfoxide ; glucose transporter 4 ; hematoxylin and eosin ; heparan sulfate proteoglycans ; high-density lipoprotein ; human umbilical vein endothelia cell ; i.p. glucose tolerance test ; lipoprotein lipase ; low-density lipoprotein ; low-density lipoprotein receptor-related protein 1 ; minimum essential medium ; peroxisome proliferator activated receptor-γ ; peroxisome proliferator response element ; phosphodiesterase 3 ; real-time polymerase chain reaction ; ribonuclease ; siRNA ; small interfering RNA ; PKA, protein kinase A ; streptozotocin ; triglyceride ; very low-density lipoproteins
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 PPARγ through the PPRE in the LRP1 promoter. Increased hepatic LRP1 may be essential for the reduction of circulating triglycerides brought about by cilostazol.
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1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Kang, Eun Seok(강은석) ORCID logo https://orcid.org/0000-0002-0364-4675
Lee, Byung Wan(이병완) ORCID logo https://orcid.org/0000-0002-9899-4992
Lee, Hyun Chul(이현철)
Cha, Bong Soo(차봉수) ORCID logo https://orcid.org/0000-0003-0542-2854
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