Vitamin E does not prevent Western diet-induced NASH progression and increases metabolic flux dysregulation in mice
Vitamin E does not prevent Western diet-induced NASH progression and increases metabolic flux dysregulation in mice
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DOI：
10.1194/jlr.ra119000183
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发表时间：
2020-05-01
影响因子：
6.5
通讯作者：
Young, Jamey D.
中科院分区：
文献类型：
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作者：
Hasenour, Clinton M.;Kennedy, Arion J.;Young, Jamey D.
脂肪肝涉及异位脂质积聚和肝脏氧化代谢失调，其可进展为称为非酒精性脂肪性肝炎（NASH）的炎症和纤维化升高的状态。控制从单纯性脂肪变性进展为NASH的因素尚不完全清楚。在这里，我们测试了膳食维生素E（VitE）补充剂可以预防NASH进展和西方饮食（WD）诱导的相关代谢改变的假设。从8周龄或20周龄开始，对高吞噬性黑皮质素-4受体缺陷（MC 4 R（-/-））小鼠喂食普通饲料、普通饲料+VitE、WD或WD+VitE。在研究结束时（28周龄），所有组均表现出广泛的肝脂肪变性。WD喂养加重了肝脏疾病的严重程度，但未诱导肝脏甘油三酯的比例变化。8周的WD加速肝脏丙酮酸循环，20周的WD广泛上调肝脏葡萄糖和氧化代谢的H-2/C-13通量分析评估。补充VitE不能减轻NASH的组织学特征。相反，WD+VitE增加了肝脏神经酰胺的丰度和饱和度，并加速代谢通量失调相比，8周的WD单独。总之，VitE并没有限制遗传性肥胖小鼠的NASH发病机制，而是增加了代谢功能障碍的一些指标。
Fatty liver involves ectopic lipid accumulation and dysregulated hepatic oxidative metabolism, which can progress to a state of elevated inflammation and fibrosis referred to as nonalcoholic steatohepatitis (NASH). The factors that control progression from simple steatosis to NASH are not fully known. Here, we tested the hypothesis that dietary vitamin E (VitE) supplementation would prevent NASH progression and associated metabolic alterations induced by a Western diet (WD). Hyperphagic melanocortin-4 receptor-deficient (MC4R(-/-)) mice were fed chow, chow+VitE, WD, or WD+VitE starting at 8 or 20 weeks of age. All groups exhibited extensive hepatic steatosis by the end of the study (28 weeks of age). WD feeding exacerbated liver disease severity without inducing proportional changes in liver triglycerides. Eight weeks of WD accelerated liver pyruvate cycling, and 20 weeks of WD extensively upregulated liver glucose and oxidative metabolism assessed by H-2/C-13 flux analysis. VitE supplementation failed to reduce the histological features of NASH. Rather, WD+VitE increased the abundance and saturation of liver ceramides and accelerated metabolic flux dysregulation compared with 8 weeks of WD alone. In summary, VitE did not limit NASH pathogenesis in genetically obese mice, but instead increased some indicators of metabolic dysfunction.