Voluntary exercise in mice fed an obesogenic diet alters the hepatic immune phenotype and improves metabolic parameters - an animal model of life style intervention in NAFLD
Voluntary exercise in mice fed an obesogenic diet alters the hepatic immune phenotype and improves metabolic parameters - an animal model of life style intervention in NAFLD
复制标题
DOI：
10.1038/s41598-018-38321-9
复制
发表时间：
2019-03-08
影响因子：
4.6
通讯作者：
Schattenberg, Joern M.
中科院分区：
文献类型：
--
作者：
Gehrke, Nadine;Biedenbach, Jana;Schattenberg, Joern M.
迫切需要可重复的动物模型来概括非酒精性脂肪性肝病（NAFLD）的病理生理，以提高对肝损伤机制的理解，并探索新的治疗方案。目前的指南建议将生活方式干预作为NAFLD的一线治疗，这些类型的干预被认为是标准治疗。目前的研究建立了一个可重复的小鼠模型，使用自愿轮转跑（VWR）对NAFLD的生活方式进行干预。雄性C57BL/6J小鼠分别饲喂高脂高碳水化合物饮食（HFD）诱导NAFLD或相应的对照饮食12周。从致肥性NAFLD饮食的第9周开始，小鼠被随机分为两组，一组自由进入跑步轮，另一组被单独关在笼子里，类似于久坐（SED）的生活方式。直到第10周，VWR诱导饲喂hfd的小鼠短暂体重减轻。与SED小鼠相比，VWR小鼠在干预结束时ALT表现正常，而代谢改变，包括空腹血糖、胰岛素、甘油三酯和总胆固醇水平升高几乎保持不变。此外，VWR通过改变关键的肝脏代谢过程，包括诱导脂肪酸β -氧化和在amp激活的蛋白激酶(AMPK)- α活性增加后抑制脂肪生成，来阻止hfd诱导的肝脏脂肪变性。肝组织中丝氨酸激酶Akt的磷酸化在VWR后增强。此外，VWR小鼠不受hfd诱导的促炎细胞因子、趋化因子表达和肝巨噬细胞浸润的影响。SED/HFD组肝核因子(NF)- κ B p65活性升高，而VWR/HFD组运动后无此活性。总之，在肥胖小鼠NAFLD模型中，体育锻炼可以改善脂肪酸和葡萄糖稳态，并保护巨噬细胞相关的肝脏炎症。
Reproducible animal models to recapitulate the pathophysiology of non-alcoholic fatty liver disease (NAFLD) are urgently required to improve the understanding of the mechanisms of liver injury and to explore novel therapeutic options. Current guidelines recommend life-style interventions as first-line therapy for NAFLD and these types of intervention are considered standard-of-care. The current study establishes a reproducible mouse model of a life-style intervention in NAFLD using voluntary wheel running (VWR). Male C57BL/6J mice were fed a high-fat, high-carbohydrate diet (HFD) to induce NAFLD or a corresponding control diet for 12 weeks. Starting at week 9 of the obesogenic NAFLD diet, mice were randomized to either free access to a running wheel or being single caged resembling a sedentary (SED) life-style. VWR induced a transient weight reduction in HFD-fed mice up until week 10. In contrast to the SED mice, VWR mice exhibited normal ALT at the end of the intervention, while the metabolic alterations including elevated fasting glucose, insulin, triglyceride, and total cholesterol levels remained almost unchanged. Additionally, VWR prevented HFD-induced hepatic steatosis by alterations in key liver metabolic processes including the induction of fatty acid beta-oxidation and lipogenesis inhibition following increased AMP-activated protein kinase (AMPK)-alpha activity. Phosphorylation of the serine kinase Akt in hepatic tissue was enhanced following VWR. Furthermore, VWR mice were protected from HFD-induced expression of pro-inflammatory cytokines, chemokines and liver macrophage infiltration. The SED/HFD group exhibited increasing activity of hepatic nuclear factor (NF)-kappa B p65, which was absent following exercise in the VWR/HFD group. In summary, in an obesogenic mouse model of NAFLD physical exercise improves fatty acid and glucose homeostasis and protects from macrophage-associated hepatic inflammation.