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Research Article
A lipidomics study reveals hepatic lipid signatures associating with deficiency of the LDL receptor in a rat model
Hong Yu Wang, Chao Quan, Chunxiu Hu, Bingxian Xie, Yinan Du, Liang Chen, Wei Yang, Liu Yang, Qiaoli Chen, Bin Shen, Bian Hu, Zhihong Zheng, Haibo Zhu, Xingxu Huang, Guowang Xu, Shuai Chen
Biology Open 2016 5: 979-986; doi: 10.1242/bio.019802
Hong Yu Wang
1State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Pukou District, Nanjing 210061, China
2Collaborative Innovation Center of Genetics and Development, Shanghai 200438, China
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  • ORCID record for Hong Yu Wang
  • For correspondence: wanghy@nicemice.cn
Chao Quan
1State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Pukou District, Nanjing 210061, China
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Chunxiu Hu
3CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian 116023, China
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Bingxian Xie
1State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Pukou District, Nanjing 210061, China
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Yinan Du
1State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Pukou District, Nanjing 210061, China
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Liang Chen
1State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Pukou District, Nanjing 210061, China
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Wei Yang
4Laboratory Animal Center, China Medical University, Shenyang 110001, China
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Liu Yang
5State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, People's Republic of China
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Qiaoli Chen
1State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Pukou District, Nanjing 210061, China
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Bin Shen
1State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Pukou District, Nanjing 210061, China
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Bian Hu
1State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Pukou District, Nanjing 210061, China
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Zhihong Zheng
4Laboratory Animal Center, China Medical University, Shenyang 110001, China
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Haibo Zhu
5State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, People's Republic of China
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Xingxu Huang
1State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Pukou District, Nanjing 210061, China
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Guowang Xu
3CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian 116023, China
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Shuai Chen
1State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Pukou District, Nanjing 210061, China
2Collaborative Innovation Center of Genetics and Development, Shanghai 200438, China
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ABSTRACT

The low-density lipoprotein receptor (LDLR) plays a critical role in the liver for the clearance of plasma low-density lipoprotein (LDL). Its deficiency causes hypercholesterolemia in many models. To facilitate the usage of rats as animal models for the discovery of cholesterol-lowering drugs, we took a genetic approach to delete the LDLR in rats aiming to increase plasma LDL cholesterol (LDL-C). An LDLR knockout rat was generated via zinc-finger nuclease technology, which harbors a 19-basepair deletion in the seventh exon of the ldlr gene. As expected, deletion of the LDLR elevated total cholesterol and total triglyceride in the plasma, and caused a tenfold increase of plasma LDL-C and a fourfold increase of plasma very low-density lipoprotein (VLDL-C). A lipidomics analysis revealed that deletion of the LDLR affected hepatic lipid metabolism, particularly lysophosphatidylcholines, free fatty acids and sphingolipids in the liver. Cholesterol ester (CE) 20:4 also displayed a significant increase in the LDLR knockout rats. Taken together, the LDLR knockout rat offers a new model of hypercholesterolemia, and the lipidomics analysis reveals hepatic lipid signatures associating with deficiency of the LDL receptor.

Footnotes

  • Competing interests

    The authors declare no competing or financial interests.

  • Author contributions

    H.Y.W., C.Q., C.H., B.X., Y.D., L.C., W.Y., L.Y. Q.C., B.S., B.H. and S.C. performed experiments, analyzed data, and reviewed the manuscript. Z.Z., H.Z., X.H. and G.X. contributed to the experimental design and reviewed the manuscript. H.Y.W. designed experiments and wrote the manuscript. All authors approved the final paper.

  • Funding

    Thanks to the Ministry of Science and Technology of the People's Republic of China [Grant Nos. 2014BAI02B01 and 2014CB964704 (the National Key Scientific Research Program of China), Grant No. 2014AA021104 (the National High Technology Research and Development Program of China)], the National Natural Science Foundation of China [Grant Nos. 31271498 and 31571211], and the Ministry of Education of the People's Republic of China [Grant Nos. 20120091120048 and NCET-13-0270] for financial support.

  • Supplementary information

    Supplementary information available online at http://bio.biologists.org/lookup/doi/10.1242/bio.019802.supplemental

  • Received May 24, 2016.
  • Accepted June 8, 2016.
  • © 2016. Published by The Company of Biologists Ltd

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.

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Keywords

  • Low-density lipoprotein receptor (LDLR)
  • Cholesterol
  • Lipid metabolism
  • Rat
  • Knockout

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Research Article
A lipidomics study reveals hepatic lipid signatures associating with deficiency of the LDL receptor in a rat model
Hong Yu Wang, Chao Quan, Chunxiu Hu, Bingxian Xie, Yinan Du, Liang Chen, Wei Yang, Liu Yang, Qiaoli Chen, Bin Shen, Bian Hu, Zhihong Zheng, Haibo Zhu, Xingxu Huang, Guowang Xu, Shuai Chen
Biology Open 2016 5: 979-986; doi: 10.1242/bio.019802
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Research Article
A lipidomics study reveals hepatic lipid signatures associating with deficiency of the LDL receptor in a rat model
Hong Yu Wang, Chao Quan, Chunxiu Hu, Bingxian Xie, Yinan Du, Liang Chen, Wei Yang, Liu Yang, Qiaoli Chen, Bin Shen, Bian Hu, Zhihong Zheng, Haibo Zhu, Xingxu Huang, Guowang Xu, Shuai Chen
Biology Open 2016 5: 979-986; doi: 10.1242/bio.019802

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