Regulation of Hepatic Cholesteryl Ester Transfer Protein Expression and Reverse Cholesterol Transport by Inhibition of DNA Topoisomerase II.
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.
From the State Key Laboratory of Medicinal Chemical Biology, Colleges of Life Sciences and.
Mengyang
M
Liu
From the State Key Laboratory of Medicinal Chemical Biology, Medicine, and Collaborative Innovation Center for Biotherapy, Nankai University, Tianjin 300071, China.
Yuanli
Y
Chen
Colleges of Life Sciences and.
Ling
L
Zhang
Colleges of Life Sciences and.
Qixue
Q
Wang
Colleges of Life Sciences and.
Xingzhe
X
Ma
Colleges of Life Sciences and.
Xiaoju
X
Li
Medicine, and Collaborative Innovation Center for Biotherapy, Nankai University, Tianjin 300071, China.
Rong
R
Xiang
Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China.
Yan
Y
Zhu
Taishan Medical University, Taian 271000, China, and.
Shucun
S
Qin
Taishan Medical University, Taian 271000, China, and.
Yang
Y
Yu
State University of New York Downstate Medical Center, New York, New York 11203.
Xian-cheng
XC
Jiang
From the State Key Laboratory of Medicinal Chemical Biology, Colleges of Life Sciences and Collaborative Innovation Center for Biotherapy, Nankai University, Tianjin 300071, China, yajundun@nankai.edu.cn.
Yajun
Y
Duan
From the State Key Laboratory of Medicinal Chemical Biology, Colleges of Life Sciences and Collaborative Innovation Center for Biotherapy, Nankai University, Tianjin 300071, China, jihonghan2008@nankai.edu.cn.
Jihong
J
Han
D000818:Animals; D002784:Cholesterol / Q000378:metabolism*; D053480:Cholesterol Ester Transfer Proteins / Q000235:genetics* / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D005047:Etoposide / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D056945:Hep G2 Cells; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D057093:Orphan Nuclear Receptors / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D013713:Teniposide / Q000494:pharmacology*; D059005:Topoisomerase II Inhibitors / Q000494:pharmacology*; D015533:Transcriptional Activation / Q000187:drug effects
D053480:Cholesterol Ester Transfer Proteins; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D059005:Topoisomerase II Inhibitors; D005047:Etoposide; D013713:Teniposide; D002784:Cholesterol; D004250:DNA Topoisomerases, Type II
CETP; LXR; RCT; Topo II inhibitor; liver