Hepatic steatosis, inflammation, and ER stress in mice maintained long term on a very low-carbohydrate ketogenic diet
Hepatic steatosis, inflammation, and ER stress in mice maintained long term on a very low-carbohydrate ketogenic diet
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DOI：
10.1152/ajpgi.00539.2010
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发表时间：
2011-06-01
影响因子：
4.5
通讯作者：
Crawford, Peter A.
中科院分区：
文献类型：
--
作者：
Garbow, Joel R.;Doherty, Jason M.;Crawford, Peter A.
低碳水化合物饮食被用来控制肥胖、癫痫和中枢神经系统的恶性肿瘤。这些饮食创造了一个独特的，但不完全定义的，细胞，分子和综合代谢状态。在这里，我们确定了长期给予极低碳水化合物、低蛋白质和高脂肪生酮饮食对C57BL/6J小鼠的系统和肝脏的影响，并将这些影响与高单一碳水化合物、高脂肪的西方饮食和低脂肪、富含多糖的对照饮食进行了对比。使用体内磁共振波谱法对身体组成、血清代谢物和肝内脂肪含量进行纵向测量，结果显示，喂食生酮饮食12周以上的小鼠仍保持苗条、血糖正常和低胰岛素水平，但肝脏脂质积累的时间模式与喂食西方饮食的小鼠截然不同。生酮饮食喂养的小鼠最终会出现全身性葡萄糖耐受不良、肝内质网应激、脂肪变性、细胞损伤和巨噬细胞积聚，但令人惊讶的是，胰岛素诱导的肝脏Akt磷酸化和全身胰岛素反应性并未受损。此外，尽管两种高脂肪饮食都增加了肝脏Pparg mRNA的丰度，但每种饮食都赋予了剪接变异的特异性。小鼠长期服用这种低碳水化合物、低蛋白生酮饮食所产生的独特营养环境，引起了非酒精性脂肪性肝病和全身葡萄糖稳态的独特特征。
Low-carbohydrate diets are used to manage obesity, seizure disorders, and malignancies of the central nervous system. These diets create a distinctive, but incompletely defined, cellular, molecular, and integrated metabolic state. Here, we determine the systemic and hepatic effects of long-term administration of a very low-carbohydrate, low-protein, and high-fat ketogenic diet, serially comparing these effects to a high-simple-carbohydrate, high-fat Western diet and a low-fat, polysaccharide-rich control chow diet in C57BL/6J mice. Longitudinal measurement of body composition, serum metabolites, and intrahepatic fat content, using in vivo magnetic resonance spectroscopy, reveals that mice fed the ketogenic diet over 12 wk remain lean, euglycemic, and hypoinsulinemic but accumulate hepatic lipid in a temporal pattern very distinct from animals fed the Western diet. Ketogenic diet-fed mice ultimately develop systemic glucose intolerance, hepatic endoplasmic reticulum stress, steatosis, cellular injury, and macrophage accumulation, but surprisingly insulin-induced hepatic Akt phosphorylation and whole-body insulin responsiveness are not impaired. Moreover, whereas hepatic Pparg mRNA abundance is augmented by both high-fat diets, each diet confers splice variant specificity. The distinctive nutrient milieu created by long-term administration of this low-carbohydrate, low-protein ketogenic diet in mice evokes unique signatures of nonalcoholic fatty liver disease and whole-body glucose homeostasis.