Abstract
Apolipoprotein E (ApoE), an essential plasma apolipoprotein, has three isoforms (E2, E3, and E4) in humans. E2 is associated with type III hyperlipoproteinemia. E4 is the major susceptibility gene to Alzheimer’s disease (AD) and coronary heart disease (CHD). We investigated lipid metabolism and atherosclerotic lesions of novel humanized ApoE knockin (hApoE KI) rats in comparison to wide-type (WT) and ApoE knockout (ApoE KO) rats. The hApoE2 rats showed the lowest bodyweight and white fat mass. hApoE2 rats developed higher serum total cholesterol (TC), total triglyceride (TG), and low- and very low density lipoprotein (LDL-C&VLDL-C). ApoE KO rats also exhibited elevated TC and LDL-C&VLDL-C. Only mild atherosclerotic lesions were detected in hApoE2 and ApoE KO aortic roots. Half of the hApoE2 rats developed hepatic nodular cirrhosis. A short period of the Paigen diet (PD) treatment led to the premature death of the hApoE2 and ApoE KO rats. Severe vascular wall thickening of the coronary and pulmonary arteries was observed in 4-month PD-treated hApoE4 rats. In conclusion, hApoE2 rats develop spontaneous hyperlipidemia and might be suitable for studies of lipid metabolism-related diseases. With the PD challenge, hApoE4 KI rats could be a novel model for the analysis of vascular remodeling.
Highlights
IntroductionApolipoprotein E (ApoE) is one of the most important plasma apolipoproteins involved in the metabolism of fats
We found a nodular change in the liver of hApoE2 rats
Our results reveal that polymorphic human Apolipoprotein E (ApoE) proteins have diverse influences on lipid profiles and plaque formation, and their impacts on vascular remodeling in response to the Paigen diet (PD) are different in rat models
Summary
Apolipoprotein E (ApoE) is one of the most important plasma apolipoproteins involved in the metabolism of fats. It is synthesized and secreted from a variety of tissues, including the liver, brain, adipose tissue, adrenal gland, muscle tissue, arterial wall, and monocytes/macrophages, but is derived primarily from the liver [1,2]. ApoE interacts with these receptors and other proteins promoting the endocytic clearance of blood lipoproteins. Besides lipid transportation, this protein is involved in non-lipid-related functions, including glucose homeostasis, immunoregulation, oxidation, and cell proliferation and migration [5,6]
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