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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