The Ossabaw pig as a model for diet induced atherosclerosis and statin responsiveness

Authors: MATTHAN, NIRUPA - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; Solano-Aguilar, Gloria; LAMON-FAVA, STEFANIA - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; GOLDBAUM, AUDREY - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; WALKER, MAURA - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; MENG, HUICUI - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; STANLEY, JAMES - Alizee Pathology , Llc; Jang, Saebyeol; Lakshman, Sukla; Molokin, Aleksey; XIE, YUE - Sichuan University; Beshah, Ethiopia; Urban, Joseph; LICHTENSTEIN, ALICE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University

Submitted to: Journal of Federation of American Societies for Experimental Biology
Publication Type: Abstract Only
Publication Acceptance Date: 11/17/2016
Publication Date: 4/23/2016
Citation: Matthan, N.R., Solano Aguilar, G., Lamon-Fava, S., Goldbaum, A., Walker, M., Meng, H., Stanley, J., Jang, S., Lakshman, S., Molokin, A., Xie, Y., Beshah, E., Urban Jr, J.F., Lichtenstein, A.H. 2016. The Ossabaw pig as a model for diet induced atherosclerosis and statin responsiveness. Journal of Federation of American Societies for Experimental Biology. 31(1):140.4.

Interpretive Summary:

Technical Abstract: Background and Objectives: The Ossabaw pig has been established as a model for obesity, metabolic syndrome, atherosclerosis and non-alcoholic steatohepatitis, when fed an extreme diet (high trans fat and fructose) in caloric excess. To increase the translational nature of this model, we determined if the pigs manifested cardiometabolic risk factors and atherosclerosis when fed diets designed to provide macronutrients in quantities typically consumed by humans (fat: 38% energy [E], carbohydrate: 45%E, protein: 15%E), and resembling human dietary patterns. Specifically, an isocaloric "Western Diet" (WD) high in saturated fat, cholesterol and refined grains was compared to a "Heart Healthy Diet" (HHD) high in unsaturated fat [omega-3 and omega-6 fatty acids], whole grain, fruits/vegetables and fiber. We also evaluated the role of atorvastatin (S) therapy in modulating these effects. Methods: Thirty male and female Ossabaw pigs were randomized into 4 groups: WD [n=7]; WD+S [n=8]; HHD [n=7]; and HHD+S [n=8]) at 3 months of age and fed the respective diets for 6 months, with S provided during the last 3 months. Body composition was determined using dual x-ray absorptiometry, serum fatty acid (FA) profiles by gas chromatography, cardiometabolic risk profile by standard procedures and degree of atherosclerosis by histopathology. Results: Serum FA profiles reflected the predominant dietary FA. Compared to pigs fed the WD, reductions in LDL-C (-45%, -77%, -86%), HDL-C (-0.1%, -31%, -50%), triglycerides (-48%, -30%, -51%), hsCRP (-30%, -39%, -28%) and alkaline phosphatase (-3%, -33%, -45%) were observed in pigs fed the WD+S, HHD and HHD+S, respectively (p<0.05, WD and WD+S vs. HHD and HHD+S). No significant effect was observed in serum glucose, insulin, TNFalpha, other liver and muscle enzyme levels, and body weight/fat distribution among groups. Histopathological evaluation documented early atherosclerotic changes in the right coronary (RC), left anterior descending (LAD) and left circumflex coronary arteries classifiable as Stary Type I (early lesions with intimal thickening), Type II (fatty streak, foam cells, macrophages) and Type III (pre-atheroma with extracellular lipid droplets) lesions, as well as greater lipid deposition (stained area %) in the aortic arch and thoracic aorta of pigs fed the WD relative to the HHD groups. A lower degree of lesion formation was observed in the RC, LAD and aortic arch of pigs fed the WD+S (p<0.05). Conclusions: These data document for the first time that Ossabaw pigs manifested a dyslipidemic profile accompanied by early stage atherosclerosis with similar pathogenesis to humans when fed a WD compared to a HHD, which was moderately reduced by S therapy. This presents a new model to examine mechanistic pathways of dietary interventions and/or diet-drug interactions in atherosclerosis development.