Atherogenesis and metabolic dysregulation in LDL receptor–knockout rats
Srinivas D. Sithu, … , Aruni Bhatnagar, Sanjay Srivastava
Srinivas D. Sithu, … , Aruni Bhatnagar, Sanjay Srivastava
Published May 4, 2017
Citation Information: JCI Insight. 2017;2(9):e86442. https://doi.org/10.1172/jci.insight.86442.
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Research Article Cardiology Vascular biology

Atherogenesis and metabolic dysregulation in LDL receptor–knockout rats

Abstract

Mechanisms of atherogenesis have been studied extensively in genetically engineered mice with disturbed cholesterol metabolism such as those lacking either the LDL receptor (Ldlr) or apolipoprotein E (apoe). Few other animal models of atherosclerosis are available. WT rabbits or rats, even on high-fat or high-cholesterol diets, develop sparse atherosclerotic lesions. We examined the effects of Ldlr deletion on lipoprotein metabolism and atherosclerotic lesion formation in Sprague-Dawley rats. Deletion of Ldlr resulted in the loss of the LDLR protein and caused a significant increase in plasma total cholesterol and triglycerides. On normal chow, Ldlr-KO rats gained more weight and were more glucose intolerant than WT rats. Plasma proprotein convertase subtilisin kexin 9 (PCSK9) and leptin levels were higher and adiponectin levels were lower in KO than WT rats. On the Western diet, the KO rats displayed exaggerated obesity and age-dependent increases in glucose intolerance. No appreciable aortic lesions were observed in KO rats fed normal chow for 64 weeks or Western diet for 16 weeks; however, after 34–52 weeks of Western diet, the KO rats developed exuberant atherosclerotic lesions in the aortic arch and throughout the abdominal aorta. The Ldlr-KO rat may be a useful model for studying obesity, insulin resistance, and early-stage atherosclerosis.

Authors

Srinivas D. Sithu, Marina V. Malovichko, Krista A. Riggs, Nalinie S. Wickramasinghe, Millicent G. Winner, Abhinav Agarwal, Rihab E. Hamed-Berair, Anuradha Kalani, Daniel W. Riggs, Aruni Bhatnagar, Sanjay Srivastava

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Figure 2

Plasma lipoproteins in Ldlr-KO rats.

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Plasma lipoproteins in Ldlr-KO rats. Lipoprotein profiles of WT and Ldlr...
Lipoprotein profiles of WT and Ldlr-KO rats maintained on normal chow (NC) for 64 weeks. (A) Representative chromatogram of the separation of lipoproteins on fast protein liquid chromatography (FPLC) on a Superose 6 column equilibrated with PBS. Plasma was applied to the column, and samples were eluted isocratically with PBS. Cholesterol recovered in FPLC eluate (0.5 ml fractions) was measured as described in Methods. Data show levels of cholesterol in 125 ml WT and 50 ml KO plasma. (B) Abundance of total lipoproteins in the plasma (n = 5/group). (C and D) Levels of total apolipoprotein B (apoB) in the plasma (n = 6–8/group) and relative distribution of apoB100 and apoB48 in the VLDL obtained from delipidated plasma (pooled from 5 rats/group), separated on 3% SDS-PAGE and silver stained. (E and F) Plasma apolipoprotein A-V (apoA-V) levels and lipoprotein lipase activity, respectively (n = 5–8/group). Unpaired 2-tailed Student’s t test was used for data analyses. Values are mean ± SEM. *P < 0.05 vs. WT rats.