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

doi:10.1242/bio.019802

A lipidomics study reveals hepatic lipid signatures associating with deficiency of the LDL receptor in a rat model

Biol Open. 2016 Jul 15;5(7):979-86. doi: 10.1242/bio.019802.

Authors

Hong Yu Wang¹, Chao Quan², Chunxiu Hu³, Bingxian Xie², Yinan Du², Liang Chen², Wei Yang⁴, Liu Yang⁵, Qiaoli Chen², Bin Shen², Bian Hu², Zhihong Zheng⁴, Haibo Zhu⁵, Xingxu Huang², Guowang Xu³, Shuai Chen⁶

Affiliations

¹ State 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 Collaborative Innovation Center of Genetics and Development, Shanghai 200438, China wanghy@nicemice.cn.
² State 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.
³ CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian 116023, China.
⁴ Laboratory Animal Center, China Medical University, Shenyang 110001, China.
⁵ State 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.
⁶ State 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 Collaborative Innovation Center of Genetics and Development, Shanghai 200438, China.

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.

Keywords: Cholesterol; Knockout; Lipid metabolism; Low-density lipoprotein receptor (LDLR); Rat.