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. 2016 Dec 6;7(49):80223-80237.
doi: 10.18632/oncotarget.12831.

Glycine protects against high sucrose and high fat-induced non-alcoholic steatohepatitis in rats

Xin Zhou  1 , Dewu Han  1 , Ruiling Xu  1 , Huiwen Wu  1   2 , Chongxiao Qu  3 , Feng Wang  1 , Xiangyu Wang  4 , Yuanchang Zhao  1
Affiliations

Glycine protects against high sucrose and high fat-induced non-alcoholic steatohepatitis in rats

Xin Zhou et al. Oncotarget. .

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.

Keywords: Pathology Section; endoplasmic reticulum stress; glycine; intestinal endotoxin; non-alcoholic steatohepatitis; oxidative stress.

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Conflict of interest statement

CONFLICTS OF INTEREST

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1. Changes in pathology, apoptosis, CD68+, ROS, the expression of p-JNK1 /JNK1, IKKβ, GRP78, and CHOP in NASH rats
Fig1.1 Pathological changes in the liver of NASH rats. control group A., 4th week group B., 12th week group C., 24th week group D.. Fig1.2 Liver apoptosis in NASH rats. control group A., 4th week group B., 12th week group C., 24th week group D., statistical analysis of apoptosis E.. Fig1.3 CD68+ changes in the liver of NASH rats. control group A., 4th week group B., 12th week group C., 24th week group D., statistical analysis of CD68+ staining. E.. Fig1.4 ROS changes in the liver of NASH rats. control group A., 4th week group B., 12th week group C., 24th week group D., statistical analysis of CD68+ staining. E.. Fig 1.5 The expression of p-JNK1 /JNK1, IKKB, Grp78, and CHOP in the livers of NASH rats. The protein expression of JNK1, p-JNK, IKKB, Grp78, and CHOP in livers via Western Blot A., statistical analysis of p-JNK/ JNK1expression levels in NAFLD rats B., statistical analysis of IKKB expression levels in NAFLD rats C., statistical analysis of Grp78 expression levels in NAFLD rats D., statistical analysis of CHOP expression levels in NAFLD rats E.. Data represents means ± standard error (n = 8). “*”indicates a statistically significant difference (P < 0.05).
Figure 2
Figure 2. Correlation analysis of LPS vs IR, TG, FFA, ALT, TNFα, MCP-1, Apoptosis, CD68, ROS, P-JNK/JNK, IKK β, GRP78, and CHOP
Correlation analysis of LPS vs indexes of NASH rats in 4 weeks A.. Correlation analysis of LPS vs indexes of NASH rats in 12 weeks B.. Correlation analysis of LPS vs indexes of NASH rats in 24 weeks C..
Figure 3
Figure 3. Effect of glycine treatment on LPS, biochemistry, and systemic inflammation indexes
Standard control group (C), high fat and high sugar group (H), high fat and high sugar + glycine group (H+G), glycine group (G). Data represents mean ± standard error (n = 8). “*”indicates a statistically significant difference (P < 0.05).
Figure 4
Figure 4. Effect of glycine treatment on liver pathology
Standard control group (C), high fat and high sugar group (H), high fat and high sugar + glycine group (H+G), glycine group (G).
Figure 5
Figure 5. Effect of glycine treatment on hepatocyte apoptosis
Standard control group (C), high fat and high sugar group (H), high fat and high sugar + glycine group (H+G), glycine group (G). “*”indicates a statistically significant difference (P < 0.05). Data represents mean ± standard error (n = 8).
Figure 6
Figure 6. Effect of glycine treatment on macrophage infiltration
Standard control group(C), high fat and high sugar group (H), high fat and high sugar + glycine group (H+G), glycine group (G). “*”indicates a statistically significant difference (P < 0.05).Data represents mean ± standard error (n = 8).
Figure 7
Figure 7. Effect of glycine treatment on oxidative stress
Standard control group (C), high fat and high sugar group (H), high fat and high sugar + glycine group (H+G), glycine group (G). “*”indicates a statistically significant difference (P < 0.05). Data represents mean ± standard error (n = 8).
Figure 8
Figure 8. Effect of glycine treatment on endoplasmic reticulum stress
Standard control group (C), high fat and high sugar group (H), high fat and high sugar + glycine group (H+G), glycine group (G). “*”indicates a statistically significant difference (P < 0.05). Data represents mean ± standard error (n= 8).
Figure 9
Figure 9. Effect of intestinal endotoxemia in the pathogenesis of NASH
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