Abstract
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.
Highlights
The number of patients with non-alcoholic fatty liver disease (NAFLD) is increasing in both developed and developing countries, and this is associated with unhealthy lifestyle habits, including poor eating habits and lack of exercise[1,2,3]
The present study showed that an HFC diet increased the expressions of autophagy-related signalling such as Atg factors, light chain 3 (LC3)-II/I and VPS34, which appeared to enhance autophagy signalling, while it suppressed the expression of p-IRE-1, p-protein kinase RNA-like ER kinase (PERK) and beclin-1, suggesting that the diet can inhibit autophagosome–lysosome fusion and proteasomal degradation
LC3-II is used as a marker of autophagy[30]
Summary
The number of patients with non-alcoholic fatty liver disease (NAFLD) is increasing in both developed and developing countries, and this is associated with unhealthy lifestyle habits, including poor eating habits and lack of exercise[1,2,3]. We previously developed an animal model for NASH using stroke-prone spontaneously hypertensive rats (SHRSP5/Dmcr)[5] When these rats were fed a high-fat and high-cholesterol (HFC) diet, they showed steatohepatitis in the liver after 2 weeks, ballooning hepatocytes, Mallory–Denk bodies and fibrosis after 8 weeks and honeycomb fibrosis after 14 weeks. An HFC diet increased the serum levels of inflammatory cytokines and tumour necrosis factor-α (TNFα) and induced a signalling network that included nuclear factor-kappa B, mitogen-activated protein kinase and nuclear factor erythroid 2-related factor 2 in the liver[6,7]. An HFC diet increased the expressions of proteins involved in fibrosis development such as transforming growth factor-β1, alpha smooth muscle actin, and collagen type I, alpha-18–11 The upregulation of these proteins was observed in the serum/liver of patients NASH1,12. It is well known that autophagy breakdown can induce damage[20]
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