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Human scavenger receptor class b type 1 is regulated by activators of peroxisome proliferators-activated receptor-γ in hepatocytes

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Abstract

High-density lipoprotein (HDL) particles play a critical role in cholesterol metabolism. The hepatic scavenger receptor class B type I (SR-B1) binds HDL particles for mediating reverse cholesterol transport (RCT), thus lowering the risk of atherosclerosis. Thiazolidinediones (TZDs), known to have potent enhancing effects on insulin sensitivity, have been developed for the treatment of non-insulin-dependent diabetes mellitus. They are a high-affinity ligand for the peroxisome proliferator-activated receptor gamma (PPAR-γ), which belongs to a nuclear receptor superfamily. In this study, we examined the effects of thiazolidinedione PPAR-γ on hepatic SR-B1 gene expression in human hepatoma G2 cell-line (HepG2). Results showed that hepatic SR-B1 mRNA and protein were increased on exposure to thiazolidinediones. Transcriptional activity of human SR-B1 (hSR-B1) gene paralleled the endogenous expression of the gene and was dependent on the dose of thiazolidinediones. We investigated the influence on the promoter activity of vector expressing PPAR and retinoid X receptor (RXR), cotransfected into the HepG2 cells along with SR-B1 promoter–reporter gene constructs. PPAR-γ and RXR sufficiently induced the SR-B1 promoter activity in the HepG2 cells. Chromatin immunoprecipitation (ChIP) assay confirmed the binding of the PPAR-γ to the SR-B1 promoter region. The mutagenesis of this binding site abolished the ability of the thiazolidinediones or PPARs to stimulate promoter activity. Together, these results indicate that the stimulation of SR-B1 expression in the liver is mediated in part by activation of the PPAR-γ and RXR, and raise the possibility that this stimulation using thiazolidinediones conditions provides a protective mechanism for accelerated atherosclerosis in diabetes mellitus.

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Acknowlegments

This wok was supported in part by Grant-in-Aid for Scientific Research 20591081 (K. Murao) and Grant-in-Aid for Scientific Research 17590937 (T. Ishida, K. Murao). We thank Ms Kazuko Yamaji and Kiyo Ueeda for their technical assistance.

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Authors and Affiliations

  1. Division of Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe Miki-cho, Kita-gun, Kagawa, 761-0793, Japan

    Rania Abdel Muneem Ahmed, Koji Murao, Hitomi Imachi, Xiao Yu, Junhun Li & Toshihiko Ishida

  2. Departments of Medicine and Biochemistry & Molecular Biology, Faculty of Medicine, University of Calgary, Health Sciences Center, 3330 Hospital Drive NW, Calgary, AB, T2N 4N1, Canada

    Norman C. W. Wong

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  1. Rania Abdel Muneem Ahmed
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  2. Koji Murao
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Correspondence to Koji Murao.

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Ahmed, R.A.M., Murao, K., Imachi, H. et al. Human scavenger receptor class b type 1 is regulated by activators of peroxisome proliferators-activated receptor-γ in hepatocytes. Endocr 35, 233–242 (2009). https://doi.org/10.1007/s12020-008-9142-2

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