Responsive Elements for Peroxisome Proliferator–Activated Receptor Are Involved in the Regulation of Phospholipid Transfer Protein
Phospholipid transfer protein (PLTP) plays an important role in human plasma HDL metabolism. Clinical data have recently indicated that plasma PLTP activity and mass were both higher in diabetic patients concomitant with hyperglycemia. The present study shows that high glucose increases both PLTP mRNA and functional activity in HepG2 cells, due to a significant increase in the promoter activity of human PLTP gene. The glucose-responsive elements are located between −759 and −230 of the PLTP 5′-flanking region, within which two binding motifs (−537 to –524 and −339 to –327) for either peroxisome proliferator–activated receptor or farnesoid X-activated receptor are involved in this glucose-mediated transcriptional regulation. This finding suggests that high glucose upregulates the transcription of human PLTP gene via nuclear hormone receptors. In addition, high glucose increases mRNA levels for several genes that are functionally important in HDL metabolism, including human ATP-binding cassette transporter A1, apolipoprotein A-I, scavenger receptor BI, and hepatic lipase. The functional promoter activities of these genes are enhanced by high glucose in three cell lines tested, indicating that glucose may also regulate these genes at the transcriptional level. Our findings provide a molecular basis for a role of hyperglycemia in altered HDL metabolism.
Address correspondence and reprint requests to Dr. An-Yue Tu, Department of Medicine, Box 358750, Northwest Lipid Research Laboratories, University of Washington, 2121 N. 35th St., Seattle, WA 98103. E-mail:.
Received for publication 31 January 2001 and accepted in revised form 26 April 2001.
ABCA1, ATP-binding cassette transporter A1; apo, apolipoprotein; CETP, cholesterol ester transfer protein; DMEM, Dulbecco’s modified Eagle’s medium; FCS, fetal calf serum; FXR, farnesoid X-activated receptor; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; HL, hepatic lipase; kb, kilobase pairs; LCAT, lecithin-cholesterol acyltransferase; LPL, lipoprotein lipase; LXR, liver X-activated receptor; PCR, polymerase chain reaction; PLTP, phospholipid transfer protein; PPAR, peroxisome proliferator–activated receptor; RT-PCR, reverse transcriptase–polymerase chain reaction; RXR, retinoid X-activated receptor; SR-BI, scavenger receptor type BI; SREBP-1, sterol regulatory element binding protein-1.