Abstract
ABSTRACTThe 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.
Highlights
As a vital lipid in the body, cholesterol maintains the structural integrity and fluidity of cellular membranes and functions as an important precursor for the biosynthesis of bile acids and steroid hormones
In this study, we generated a lowdensity lipoprotein (LDL) receptor (LDLR) knockout rat that has a significant increase in plasma total cholesterol (TC) and TG, displayed an elevated plasma LDL cholesterol (LDL-C) and that can be used as a new animal model of hypercholesterolemia
ApoB-48 containing chylomicron remnants can be efficiently cleared in an apoE dependent manner in the absence of the LDLR, which is mediated by the LDLR-related protein (LRP) (Ishibashi et al, 1994b; Rubinsztein et al, 1990)
Summary
As a vital lipid in the body, cholesterol maintains the structural integrity and fluidity of cellular membranes and functions as an important precursor for the biosynthesis of bile acids and steroid hormones. Cholesterol levels have to be maintained tightly, and too much cholesterol (hypercholesterolemia) increases the risks of atherosclerosis and coronary heart disease (Narverud et al, 2014). Cholesterol, together with triacylglycerides (TAG) and other fats, is packed with apolipoprotein B and additional. There are five types of lipoproteins according to their sizes, i.e. chylomicrons, very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), lowdensity lipoprotein (LDL) and high-density lipoprotein (HDL), among which LDL increases while HDL decreases the risks of atherosclerosis and coronary heart disease (Brunham and Hayden, 2015; Ishibashi et al, 1994a). The clearance of plasma LDL is mediated by the LDL receptor (LDLR) (Brown and Goldstein, 1986; Ishibashi et al, 1993), whose deficiency in human causes a massive elevation of plasma TC (600-1000 mg/dl) and leads to fulminant atherosclerosis (Goldstein and Brown, 1989)
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