Upregulation of hepatic LRP1 by rosiglitazone: a possible novel mechanism of the beneficial effect of thiazolidinediones on atherogenic dyslipidemia.
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.
Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, 250 Seongsanno, Seodaemun-gu, Seoul 120-752, Republic of Korea.
Jae Hoon
JH
Moon
Hyung Jun
HJ
Kim
Hyun Min
HM
Kim
Ae Hee
AH
Yang
Byung-Wan
BW
Lee
Eun Seok
ES
Kang
Hyun Chul
HC
Lee
Bong Soo
BS
Cha
D000818:Animals; D050171:Dyslipidemias / Q000188:drug therapy* / Q000378:metabolism*; D056945:Hep G2 Cells; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000627:therapeutic use*
D026503:Low Density Lipoprotein Receptor-Related Protein-1; D045162:Thiazolidinediones; D000077154:Rosiglitazone