Atherogenesis and metabolic dysregulation in LDL receptor-knockout rats

• Published in: JCI insight 2017-05, Vol.2 (9)
• Main Authors: Sithu, Srinivas D, Malovichko, Marina V, Riggs, Krista A, Wickramasinghe, Nalinie S, Winner, Millicent G, Agarwal, Abhinav, Hamed-Berair, Rihab E, Kalani, Anuradha, Riggs, Daniel W, Bhatnagar, Aruni, Srivastava, Sanjay
• Format: Article
• Language: English
• ISSN: 2379-3708; 2379-3708
• DOI: 10.1172/jci.insight.86442

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.