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.

Lipoprotein lipase preparations were obtained by aqueous extraction of various tissues from sheep and rats. Preparations having high activity towards serum-activated triolein emulsions were obtained from actively growing sheep, provided that the tissue was maintained at 37�C throughout the extraction procedure. Activity of lipoprotein lipase from sheep adipose tissue, like that from the rat, was dependent upon the presence of serum in the reaction mixture, and was optimal at pH 8-9. Inhibition of sheep adipose tissue preparations by protamine sulfate (1 mg/ml) and O' 6 M NaCl was similar to that found for rat adipose tissue preparations. The affinity of the lipoprotein lipase preparation for the activated substrate from sheep and rat adipose tissue was, however, markedly different; sheep preparations being activated at much lower substrate concentrations (Km O' 43 mM) than rat preparations (Km > 5 mM). These findings, confirmed with acetone--ether preparations of lipoprotein lipase, indicate that the enzyme from sheep adipose tissue has a greater potential to remove triacylglycerol from the plasma. This could result in a greater deposition of fat in the tissue.

Apolipoprotein E (ApoE) is one of the essential plasma apolipoproteins involved majorly in lipids’ metabolism. Human ApoE has three isoforms (E2, E3, and E4) differing by one or two amino acids. E3 is the most common one with a population allelic frequency of 78% and considered normal. E2 (7%) is associated with genetic disorder type III hyperlipoproteinemia. E4 (15%) is the major susceptibility gene related to the onset of Alzheimer's disease (AD) and cardiovascular diseases (CVDs). Gene modified mice carrying a mutant ApoE gene or different ApoE isoforms, such as ApoE knockout (ApoE KO) mouse and humanized ApoE knockin (hApoE KI) mice, provide a series of beneficial mouse models in the studies of atherosclerosis, hyperlipidemia, and AD. However, alternative animal models are necessary to investigate the roles and underlying mechanisms of ApoE in human diseases. Recently, the novel hApoE KI rat models created by Envigo RMS, Saint Louis, MO (preciously named Horizon Discovery and SAGE Labs respectively) by replacing endogenous rat ApoE with human ApoE2, E3, or E4 allele are available. Hypothesis The hApoE KI rats could recapitulate the diversities of metabolic phenotypes in human carrying polymorphic ApoE proteins, and will be ideal animal models to study the roles of ApoE proteins. Methods We examed the body weight, serum lipid levels, the mass of fat tissue, and vascular atherosclerotic lesions of these hApoE rat models in comparison to wide‐type Sprague Dawley (WT) and ApoE KO rats, as well as the metabolic changes, death rate, and development of vascular atherosclerosis of these rats with 4‐months atherogenic Paigen diet (PD) (40 kcal% Fat, 1.25% Cholesterol, 0.5% Cholic Acid). Results We investigate the body weight starting from week seven till month six, and found that all the hApoE KI and ApoE KO rats had a lower body weight than WT at the corresponding age. The hApoE2 KI rats showed lowest body weight. At six months (P6m), all hApoE KI and KO rats had lower anti‐atherogenic lipoprotein HDL. The total cholesterol (TC), total triacylglycerol (TG), and LDL/VLDL of hApoE2 KI rats were higher than those of WT, hApoE3 KI and hApoE4 KI rats. ApoE KO rats also exhibited elevated total cholesterol and LDL/VLDL, but not total triacylglycerol. Surprisingly, the mass of white fat was less in hApoE2 KI rats. No obvious aortic plaques were identified in the en face aortas stained by Oil Red O of all normal diet‐fed hApoE KI and ApoE KO rats at P6m. A mild atherosclerotic lesion was detected in frozen section of hApoE2 KI and ApoE KO aortic roots. After challenged with the PD, hApoE2 KI and ApoE KO rats died within two and half weeks. Causes of death were different: hApoE2 KI rats might be due to fat embolism in big vessels and heart chambers; ApoE KO rats might be caused by massive pulmonary alveolar hydrops (accompanying considerable lipid‐laden macrophages accumulated in the lung). Thicker walls of small vessels in lung and heart, as well as necrosis of cardiomyocytes, were demonstrated in hApoE4 KI rats after four m...