Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, 250 Seongsanno, Seodaemun-gu, Seoul 120-752, Republic of Korea.
J Mol Endocrinol. 2012 Oct 10;49(3):165-74. doi: 10.1530/JME-12-0119. Print 2012 Dec.
Hepatic LDL receptor-related protein 1 (LRP1) plays a role in the clearance of circulating remnant lipoproteins. In this study, we investigated the effect of rosiglitazone treatment on the expression and function of hepatic LRP1. HepG2 cells were incubated with various concentrations of rosiglitazone. Male Long-Evans Tokushima Otsuka (LETO) rats and Otsuka-Long-Evans-Tokushima Fatty (OLETF) 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 rosiglitazone in HepG2 cells. However, at concentrations above 50 μM rosiglitazone, LRP1 mRNA and protein expressions did not change compared with those in nontreated cells. Reporter assay showed that 0.5 and 5 μM rosiglitazone increased the transcriptional activity of the LRP1 promoter in HepG2 cells. The uptake of apolipoprotein E through LRP1 in HepG2 cells was also increased by rosiglitazone. Hepatic LRP1 was reduced in OLETF rats compared with that of LETO rats and rosiglitazone treatment increased hepatic LRP1 in OLETF rats. A high glucose condition (25 mM 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 could contribute to an improvement in atherogenic lipid profiles in diabetic patients.
肝 LDL 受体相关蛋白 1（LRP1）在清除循环残粒脂蛋白中发挥作用。本研究旨在探讨罗格列酮治疗对肝 LRP1 表达和功能的影响。用不同浓度的罗格列酮孵育 HepG2 细胞，雄性 Long-Evans Tokushima Otsuka（LETO）大鼠和 Otsuka-Long-Evans-Tokushima Fatty（OLETF）大鼠用罗格列酮治疗 5 周。分析 HepG2 细胞和大鼠肝组织中 LRP1 的表达和功能。0.5 和 5μM 罗格列酮可增加 HepG2 细胞中 LRP1mRNA 和蛋白表达，而浓度高于 50μM 时，与未处理细胞相比，LRP1mRNA 和蛋白表达无变化。报告基因分析显示，0.5 和 5μM 罗格列酮可增加 HepG2 细胞 LRP1 启动子的转录活性。罗格列酮还增加了 HepG2 细胞中通过 LRP1 摄取载脂蛋白 E。与 LETO 大鼠相比，OLETF 大鼠肝 LRP1 减少，罗格列酮治疗可增加 OLETF 大鼠肝 LRP1。高葡萄糖条件（培养基中 25mM 葡萄糖）降低 HepG2 细胞中 LRP1 的表达，罗格列酮可恢复这种降低的 LRP1 表达。总之，本研究数据表明，糖尿病状态下肝 LRP1 减少与致动脉粥样硬化性血脂异常的发生有关，噻唑烷二酮类药物增加肝 LRP1 可能有助于改善糖尿病患者的致动脉粥样硬化性脂质谱。
