Regulation of Hepatic Cholesteryl Ester Transfer Protein Expression and Reverse Cholesterol Transport by Inhibition of DNA Topoisomerase II

Mengyang Liu,Yuanli Chen,Ling Zhang,Qixue Wang,Xingzhe Ma,Xiaoju Li,Rong Xiang,Yan Zhu,Shucun Qin,Yang Yu,Xian-Cheng Jiang,Yajun Duan,Jihong Han

doi:10.1074/jbc.m115.643015

Abstract

Cholesteryl ester transfer protein (CETP) transfers cholesteryl esters from high density lipoprotein to triglyceride-rich lipoproteins. CETP expression can be transcriptionally activated by liver X receptor (LXR). Etoposide and teniposide are DNA topoisomerase II (Topo II) inhibitors. Etoposide has been reported to inhibit atherosclerosis in rabbits with un-fully elucidated mechanisms. In this study we determined if Topo II activity can influence cholesterol metabolism by regulating hepatic CETP expression. Inhibition of Topo II by etoposide, teniposide, or Topo II siRNA increased CETP expression in human hepatic cell line, HepG2 cells, which was associated with increased CETP secretion and mRNA expression. Meanwhile, inhibition of LXR expression by LXR siRNA attenuated induction of CETP expression by etoposide and teniposide. Etoposide and teniposide induced LXRα expression and LXRα/β nuclear translocation while inhibiting expression of receptor interacting protein 140 (RIP140), an LXR co-repressor. In vivo, administration of teniposide moderately reduced serum lipid profiles, induced CETP expression in the liver, and activated reverse cholesterol transport in CETP transgenic mice. Our study demonstrates a novel function of Topo II inhibitors in cholesterol metabolism by activating hepatic CETP expression and reverse cholesterol transport.

Highlights

Cholesteryl ester transfer protein (CETP) expression mediates cholesterol metabolism and the development of atherosclerosis
Etoposide and Teniposide Induce CETP Expression and Secretion from HepG2 Cells—To test if topoisomerase II (Topo II) inhibitors can influence CETP expression in hepatocytes, HepG2 cells were treated with etoposide or teniposide at different concentrations for 16 h followed by determination of CETP protein expression
In this study we determined that inactivation of Topo II induced hepatic CETP expression and secretion

Summary

Background

CETP expression mediates cholesterol metabolism and the development of atherosclerosis. Results: Inhibition of Topo II activates CETP expression in HepG2 cells and CETP transgenic mouse liver, which was associated with increased reverse cholesterol transport in vivo. Administration of teniposide moderately reduced serum lipid profiles, induced CETP expression in the liver, and activated reverse cholesterol transport in CETP transgenic mice. High expressing CETP can reduce atherosclerosis in the animal models [15,16,17], indicating that the anti-atherogenic properties of Topo II inhibitors are related to regulation of cholesterol metabolism, such as hepatic CETP expression. In this study we determined if Topo II inhibitors can activate CETP expression in a human hepatic cell line, HepG2 cells, and the underlying molecular mechanisms. We determined if teniposide is able to induce CETP expression in the liver and enhance RCT in the CETP transgenic mice

Experimental Procedures

Results

Discussion