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The effect of rosiglitazone on hepatic LRP1 expression : a novel mechanism of the improvement of atherogenic dyslipidemia by thiazolidinedione drugs in diabetes mellitus

Other Titles
 로지글리타존이 간의 LRP1 발현에 미치는 영향: 티아졸리딘디온 제제가 당뇨병에서 발생하는 죽상경화성 지질대사이상을 호전시키는 새로운 기전 
 Dept. of Internal Medicine (내과학교실) 
Issue Date
Dept. of Medicine/박사
Hepatic low-density lipoprotein receptor-related protein 1 (LRP1) plays an important role in the clearance of circulating remnant lipoproteins. In this study, the effect of thiazolidinedione, an insulin sensitizing drug on the expression and function of hepatic LRP1 was investigated. This study may present a novel mechanism of the improvement of atherogenic dyslipidemia by a thiazolidinedione drug in diabetic patients. For in vitro evaluation, HepG2 cells were treated with various concentrations of rosiglitazone. For in vivo study, male Otsuka Long-Evans Tokushima Fatty (OLETF) rats and Long-Evans Tokushima Otsuka (LETO) rats were used as a diabetic animal model and its normal counterpart respectively. Rats were treated with rosiglitazone for 5 weeks. The expression and function of LRP1 in HepG2 cells and liver samples of rats were analyzed.LRP1 mRNA and protein expressions were increased by 0.5 and 5 μM of rosiglitazone in HepG2 cells. However, the expression of LRP1 did not change compared to that in non-treated cells at concentrations above 50 μM of rosiglitazone. The electrophoretic mobility shift assay and the reporter assay showed that rosiglitazone increased the transcriptional activity of the LRP1 promoter by binding peroxisome proliferator-activated receptor-γ to a perxisome proliferator response element of the LRP1 promoter in HepG2 cells. The rosiglitazone-induced up-regulation of the LRP1 promoter activity showed the same tendency with the LRP1 expression. The uptake of ApoE through LRP1 in HepG2 cells was also increased by rosiglitazone. The serum triglyceride level was increased in OLETF rats compared to that in LETO rats and partially recovered with rosiglitazone treatment. Hepatic LRP1 was reduced in OLETF rats compared to that in LETO rats and rosiglitazone treatment increased the hepatic LRP1 in OLETF rats. A high-glucose condition (25 mM of glucose in culture media) reduced the expression of LRP1 in HepG2 cells, and this reduced LRP1 expression was recovered with rosiglitazone.In conclusion, our data suggest that decreased hepatic LRP1 in a diabetic condition is associated with the development of atherogenic dyslipidemia and that increased hepatic LRP1 by thiazolidinediones contributes to an improvement in atherogenic lipid profiles in diabetic patients.
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1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 3. Dissertation
Yonsei Authors
Moon, Jae Hoon(문재훈)
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