title: A lipidomics study reveals hepatic lipid signatures associating with deficiency of the LDL receptor in a rat model.
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.
authors.affiliation: 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.
authors.forename: Hong Yu
authors.identifier: http://orcid.org/0000-0002-4064-798X
authors.initials: HY
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Chao
authors.initials: C
authors.lastname: Quan
authors.affiliation: CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian 116023, China.
authors.forename: Chunxiu
authors.initials: C
authors.lastname: Hu
authors.affiliation: 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.
authors.forename: Bingxian
authors.initials: B
authors.lastname: Xie
authors.affiliation: 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.
authors.forename: Yinan
authors.initials: Y
authors.lastname: Du
authors.affiliation: 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.
authors.forename: Liang
authors.initials: L
authors.lastname: Chen
authors.affiliation: Laboratory Animal Center, China Medical University, Shenyang 110001, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Yang
authors.affiliation: 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.
authors.forename: Liu
authors.initials: L
authors.lastname: Yang
authors.affiliation: 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.
authors.forename: Qiaoli
authors.initials: Q
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Bin
authors.initials: B
authors.lastname: Shen
authors.affiliation: 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.
authors.forename: Bian
authors.initials: B
authors.lastname: Hu
authors.affiliation: Laboratory Animal Center, China Medical University, Shenyang 110001, China.
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Zheng
authors.affiliation: 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.
authors.forename: Haibo
authors.initials: H
authors.lastname: Zhu
authors.affiliation: 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.
authors.forename: Xingxu
authors.initials: X
authors.lastname: Huang
authors.affiliation: CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian 116023, China.
authors.forename: Guowang
authors.initials: G
authors.lastname: Xu
authors.affiliation: 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.
authors.forename: Shuai
authors.initials: S
authors.lastname: Chen
keywords: Cholesterol; Knockout; Lipid metabolism; Low-density lipoprotein receptor (LDLR); Rat