Abstract
We set out to explore the hypothesis that glycine attenuates non-alcoholic steatohepatitis (NASH) in rats and the possible mechanism by which is it does. Male Sprague-Dawley (SD) rats were fed a diet containing high fat and high sucrose (HSHF) for 24 weeks to induce NASH. Blood and liver tissues were sampled at selected time points throughout the study. Compared with control animals, the content of alanine transaminase (ALT), triglycerides (TGs), and free fatty acids (FFAs) in plasma and the TG and FFA content in the liver was increased from week 4 to 24. The level of TNFα and MCP-1 in plasma, the content of TNFα in the liver, the insulin resistance index, inflammatory cell infiltration, hepatocyte apoptosis, reactive oxygen species (ROS) generation, and endoplasmic stress-associated protein expression were unaltered at 4 weeks. However, these levels were significantly elevated in HSHF fed rats at 12 weeks. At the same time, the level of endotoxin progressively increased from 0.08 ± 0.02 endotoxin EU/ml at week 4 to 0.7 ± 0.19 EU/ml at week 24. Moreover, these rats had elevated blood endotoxin levels, which were positively associated with their NASH indexes. Liver histology progressively worsened over the course of the study. However, we found that with concomitant treatment with glycine, the level of endotoxin decreased, while NASH indexes significantly decreased and liver status markedly improved,. These data support the hypothesis that glycine protects against NASH in rats by decreasing the levels of intestinal endotoxin, alleviating endoplasmic reticulum and oxidative stress.
Highlights
Nonalcoholic fatty liver disease (NAFLD) is a significant health issue, as it affects up to 30% of adults and up to 10% of children in developed countries [1, 2]
Correlation analysis showed that the level of LPS in plasma was progressively elevated in non-alcoholic steatohepatitis (NASH) rats, which was positively related to elevated HOMA-IR, elevated levels of alanine transaminase (ALT), TNF-α, MCP-1 in plasma, and elevated levels of TGs, free fatty acids (FFAs), and TNF-α in liver homogenates (Figure 2A-2C)
We found that a high fat and high sucrose diet led to a significant increase in the expression ratio of p-JNK1/JNK1 in the liver by 12 weeks, yet there was no change in total JNK
Summary
Nonalcoholic fatty liver disease (NAFLD) is a significant health issue, as it affects up to 30% of adults and up to 10% of children in developed countries [1, 2]. The NAFLD disease spectrum originates from fatty deposits in the liver; 20% of the deposits progress to develop non-alcoholic steatohepatitis (NASH), which can result in fibrosis, cirrhosis, liver failure, and even liver cancer [4, 5]. The first hit refers to an accumulation of fatty acids and triglycerides within the liver. The second hit is thought to arise from chronic stresses, such as enhanced lipid peroxidation and increased generation of reactive oxygen species (ROS) [8] and elevated endoplasmic reticulum stress (ERS), the likely byproducts of exacerbated proinflammatory responses in the fatty liver [9].
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