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 cholesterollowering 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.

Spontaneous severe hypercholesterolemia and atherosclerosis lesions in rabbits with deficiency of low-density lipoprotein receptor (LDLR) on exon 7

“…They concluded that LDL receptors play a major role in the catabolism of remnant particles. Wang, H. Y. et al [ 10 ] reported the generation of LDLR-KO rat with disruption of exon 7, the deletion of the LDLR elevated total cholesterol and total triglyceride in the plasma, and caused a tenfold increase of plasma LDL and a fourfold increase of plasma VLDL on high cholesterol diet. In this study, mutations of the founder rabbit LDLR gene can be divided into two kinds: frame-shift mutation and deletion/insertion of several amino acids.…”

“…The deficiency of different genes causes hypercholesterolemia in many models, including mice [ [7] , [8] , [9] ], rats [ 10 , 11 ], and pigs [ 12 ]. Analysis of these animal models shows that changes in systemic lipid metabolism and plasma lipoproteins, and the formation of atherosclerotic lesions are variably affected.…”

“…According to LOVD, LDLR variants on exon 7 that encode EGF repeat A account for 6% of the total 1741 variants [ 20 , 28 , 29 ]. However there have been only a few reports about animal models with deficiency in the exon 7 of the LDLR gene [ 10 ].…”

The atherogenic role of immune cells in familial hypercholesterolemia

“…Since untreated FH significantly accelerates cardiovascular diseases (CVD), such as myocardial infarction, carotid atherosclerosis and coronary artery disease (CAD), it is considered as a major public health burden . Homozygous and heterozygous FH patients are characterized by extremely high, declining to moderate cholesterol levels . Approximately 1 per 200–300 persons worldwide is affected by heterozygous FH .…”

“…[8][9][10] Homozygous and heterozygous FH patients are characterized by extremely high, declining to moderate cholesterol levels. 11 Approximately 1 per 200-300 persons worldwide is affected by heterozygous FH. 12 However, the homozygous FH occurs more rarely, with an estimated prevalence of 1/160,000 to 1/300,000.…”