Cardiovascular Nutrition Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA.
Diet, Genomics, and Immunology Laboratory, USDA, Agricultural Research Service, Beltsville Human Nutrition Research Center, Beltsville, MD.
J Nutr. 2018 Apr 1;148(4):542-551. doi: 10.1093/jn/nxy002.
Animal models that mimic diet-induced human pathogenesis of chronic diseases are of increasing importance in preclinical studies. The Ossabaw pig is an established model for obesity-related metabolic disorders when fed extreme diets in caloric excess.
To increase the translational nature of this model, we evaluated the effect of diets resembling 2 human dietary patterns, the Western diet (WD) and the Heart Healthy Diet (HHD), without or with atorvastatin (-S or +S) therapy, on cardiometabolic risk factors and atherosclerosis development.
Ossabaw pigs (n = 32; 16 boars and 16 gilts, aged 5-8 wk) were randomized according to a 2 × 2 factorial design into 4 groups (WD-S, WD+S, HHD-S, and HHD+S) and were fed the respective diets for 6 mo. The WD (high in saturated fat, cholesterol, and refined grain) and the HHD (high in unsaturated fat, whole grain, and fruit and vegetables) were isocaloric [38% of energy (%E) from fat, 47%E from carbohydrate, and 15%E from protein]. Body composition was determined by using dual-energy X-ray absorptiometry, serum fatty acid (FA) profiles by gas chromatography, cardiometabolic risk profile by standard procedures, and degree of atherosclerosis by histopathology.
Serum FA profiles reflected the predominant dietary FA. Pigs fed the WD had 1- to 4-fold higher concentrations of LDL cholesterol, non-HDL cholesterol, HDL cholesterol, high-sensitivity C-reactive protein (hs-CRP), tumor necrosis factor α (TNF-α), alkaline phosphatase (ALP), and alanine aminotransferase (ALT) compared with HHD-fed pigs (all P-diet < 0.05). Statin therapy significantly lowered concentrations of LDL cholesterol (-39%), non-HDL cholesterol (-38%), and triglycerides (-6%) (P-statin < 0.02). A greater degree of atheromatous changes (macrophage infiltration, foam cells, fatty streaks) and lesion incidence was documented in the coronary arteries (P-diet < 0.05), as well as 2- to 3-fold higher lipid deposition in the aortic arch or thoracic aorta of WD- compared with HHD-fed pigs (P-diet < 0.001).
Ossabaw pigs manifested a dyslipidemic and inflammatory profile accompanied by early-stage atherosclerosis when fed a WD compared with an HHD, which was moderately reduced by atorvastatin therapy. This phenotype presents a translational model to examine mechanistic pathways of whole food-based dietary patterns on atherosclerosis development.
在临床前研究中，模拟人类疾病发病机制的动物模型对于研究肥胖相关代谢紊乱和动脉粥样硬化等慢性疾病变得越来越重要。奥萨索普猪是一种在摄入高热量、高脂肪、高胆固醇的极端饮食时会发生肥胖相关代谢紊乱的模型动物。
为了提高该模型的转化能力，我们评估了类似于两种人类饮食模式（西方饮食和心脏健康饮食）的饮食对心血管代谢危险因素和动脉粥样硬化发展的影响，同时给予阿托伐他汀（-S 或 +S）治疗。
将 32 头（16 头公猪和 16 头母猪，年龄 5-8 周）奥萨索普猪随机分为 4 组（WD-S、WD+S、HHD-S 和 HHD+S），根据 2×2 析因设计进行分组，并分别给予相应的饮食 6 个月。西方饮食（饱和脂肪、胆固醇和精制谷物含量高）和心脏健康饮食（不饱和脂肪、全谷物、水果和蔬菜含量高）的热量均相同（脂肪占总热量的 38%，碳水化合物占总热量的 47%，蛋白质占总热量的 15%）。采用双能 X 射线吸收法测定体成分，气相色谱法测定血清脂肪酸（FA）谱，采用标准方法测定心血管代谢风险谱，采用组织病理学方法测定动脉粥样硬化程度。
血清 FA 谱反映了主要的饮食 FA。与 HHD 饮食组相比，摄入 WD 的猪 LDL 胆固醇、非 HDL 胆固醇、HDL 胆固醇、高敏 C 反应蛋白（hs-CRP）、肿瘤坏死因子 α（TNF-α）、碱性磷酸酶（ALP）和丙氨酸氨基转移酶（ALT）浓度高出 1-4 倍（所有 P<0.05）。他汀类药物治疗可显著降低 LDL 胆固醇（-39%）、非 HDL 胆固醇（-38%）和甘油三酯（-6%）（P<0.02）。在冠状动脉中，WD 饮食组的动脉粥样硬化病变（巨噬细胞浸润、泡沫细胞、脂肪条纹）和病变发生率明显高于 HHD 饮食组（P<0.05），并且 WD 饮食组主动脉弓或胸主动脉的脂质沉积量也比 HHD 饮食组高出 2-3 倍（P<0.001）。
与 HHD 饮食相比，奥萨索普猪摄入 WD 时表现出血脂异常和炎症特征，同时伴有早期动脉粥样硬化，阿托伐他汀治疗可适度减轻这种表型。这种表型为研究全食物饮食模式对动脉粥样硬化发展的机制途径提供了一个转化模型。
