Upregulation of hepatic LRP1 by rosiglitazone: a possible novel mechanism of the beneficial effect of thiazolidinediones on atherogenic dyslipidemia

Abstract

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 mM rosiglitazone in HepG2 cells. However, at concentrations above 50 mM rosiglitazone, LRP1 mRNA and protein expressions did not change compared with those in nontreated cells. Reporter assay showed that 0 . 5 and 5 mM 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.

High Concentrations of Rosiglitazone Reduce mRNA and Protein Levels of LRP1 in HepG2 Cells

“…In this study, we sought to replicate previous studies and to investigate the molecular mechanism by which high concentrations of RGZ reduce LRP1 levels in HepG2 cells. Our data confirmed that transcriptional activation of LRP1 occurred in response to RGZ at 3 and 10 μM, in agreement with the study reported by Moon et al (2012a) . On the other hand, we found that high concentrations of RGZ decreased both mRNA and protein levels of LRP1.…”

“…However, RGZ has been associated with cardiovascular risks, resulting in a reconsideration of its therapeutic use ( Nissen and Wolski, 2007 ; Hiatt et al, 2013 ). Indeed, results of some studies have indicated that RGZ modulates LRP1 expression by targeting PPARγ expression in cell culture models, including the HepG2 cell line ( Gauthier et al, 2003 ; Moon et al, 2012a , b ).…”

The effects of PPARγ on the regulation of the TOMM40 - APOE - C1 genes cluster

“…Other investigators have demonstrated robust activation of PPARγ-responsive events in this concentration range [36, 63, 64]. Importantly, we detected significant inhibition of cell growth at the higher pioglitazone concentrations (20–50 µM; Supplementary Figure 2).…”

Decreased Expression of Hepatic Low-Density Lipoprotein Receptor–Related Protein 1 in Hypothyroidism: A Novel Mechanism of Atherogenic Dyslipidemia in Hypothyroidism

“…Llorente-Cortés et al (27)(28)(29) investigated the regulation of LRP1 in vascular smooth muscle cells and macrophages and reported that sterol regulatory element binding protein-2 negatively regulated LRP1 expression in macrophages (29), whereas in a previous study, we reported that sterol regulatory element binding protein-2 is a key activator of LRP1 expression in hepatocytes (30). In adipocytes, LRP1 is known to be regulated by the peroxisome proliferatoractivated receptor-c (31), and we also re-affirmed the regulation of LRP1 associated with peroxisome proliferator-activated receptor-c in human brain microvascular endothelial cells (32) and hepatocytes (33). In the present study, we demonstrate that the thyroid hormone regulates LRP1 expression in hepatocytes.…”