Human scavenger receptor class B type 1 is regulated by activators of peroxisome proliferators-activated receptor-gamma in hepatocytes.
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-gamma), which belongs to a nuclear receptor superfamily. In this study, we examined the effects of thiazolidinedione PPAR-gamma 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-gamma and RXR sufficiently induced the SR-B1 promoter activity in the HepG2 cells. Chromatin immunoprecipitation (ChIP) assay confirmed the binding of the PPAR-gamma 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-gamma and RXR, and raise the possibility that this stimulation using thiazolidinediones conditions provides a protective mechanism for accelerated atherosclerosis in diabetes mellitus.
Ahmed
Rania Abdel Muneem
RA
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.
Murao
Koji
K
Imachi
Hitomi
H
Yu
Xiao
X
Li
Junhun
J
Wong
Norman C W
NC
Ishida
Toshihiko
T
D001665:Binding Sites / Q000235:genetics; D006528:Carcinoma, Hepatocellular; D045744:Cell Line, Tumor; D002788:Cholesterol Esters / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D022781:Hepatocytes / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008113:Liver Neoplasms; D016296:Mutagenesis; D047495:PPAR gamma / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D047488:Retinoid X Receptors / Q000235:genetics / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051122:Scavenger Receptors, Class B / Q000032:analysis / Q000235:genetics*; D045162:Thiazolidinediones / Q000494:pharmacology*; D014162:Transfection
D002788:Cholesterol Esters; D047495:PPAR gamma; D012333:RNA, Messenger; D047488:Retinoid X Receptors; C495124:SCARB1 protein, human; D051122:Scavenger Receptors, Class B; D045162:Thiazolidinediones; D004247:DNA