Department of Public Health, Fujita Health University School of Medicine, Toyoake, 470-1192, Japan.
Department of General Medicine/Family & Community Medicine, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan.
Sci Rep. 2019 Aug 29;9(1):12514. doi: 10.1038/s41598-019-48973-w.
Precise molecular pathways involved in the progression of non-alcoholic steatohepatitis (NASH) remain to be elucidated. As Mallory-Denk bodies were occasionally observed in the enlarged hepatocytes in NASH model rat (SHRSP5/Dmcr) fed high-fat and high-cholesterol (HFC) diet, we aimed to clarify the roles of autophagy and endoplasmic reticulum (ER) stress in NASH progression. Male SHRSP5/Dmcr were randomly divided into 4 groups. Two groups were fed a control diet; the other two groups were fed a HFC diet for 2 and 8 weeks, respectively. The HFC diet increased the autophagy-related proteins levels and microtubule-associated protein 1 light chain 3-II/I ratio after 2 and 8 weeks, respectively. However, regarding ER stress-related proteins, the HFC diet decreased the levels of phosphorylated (p-) inositol-requiring kinase-1 (p-IRE-1) and p-protein kinase RNA-like ER kinase after 2 weeks. Additionally, the HFC diet increased anti-ubiquitin-positive cells and the level of the autophagy substrate p62, suggesting that the HFC diet induced dysfunction in ubiquitin-dependent protein degradation pathways. In conclusion, the HFC diet arrested the autophagy process in the liver; this was particularly associated with decreases in p-IRE-1 expression.
确切的参与非酒精性脂肪性肝炎（NASH）进展的分子途径仍有待阐明。由于 Mallory-Denk 体在高脂肪和高胆固醇（HFC）饮食喂养的 NASH 模型大鼠（SHRSP5/Dmcr）的增大肝细胞中偶尔被观察到，我们旨在阐明自噬和内质网（ER）应激在 NASH 进展中的作用。雄性 SHRSP5/Dmcr 被随机分为 4 组。两组喂食对照饮食；另外两组分别喂食 HFC 饮食 2 周和 8 周。HFC 饮食分别在 2 周和 8 周后增加了自噬相关蛋白的水平和微管相关蛋白 1 轻链 3-II/I 比值。然而，对于 ER 应激相关蛋白，HFC 饮食在 2 周后降低了磷酸化（p-）肌醇需求激酶-1（p-IRE-1）和 p-蛋白激酶 RNA 样内质网激酶的水平。此外，HFC 饮食增加了抗泛素阳性细胞和自噬底物 p62 的水平，表明 HFC 饮食诱导了泛素依赖性蛋白降解途径的功能障碍。总之，HFC 饮食阻断了肝脏中的自噬过程；这与 p-IRE-1 表达的降低特别相关。
