Glycine Protects Against Non-Alcoholic Hepatitis by Downregulation of the TLR4 Signaling Pathway.

Objective: To evaluate the effect of glycine on regulation of the hepatic toll-like receptor 4 (TLR4) signaling pathway by metabolic endotoxemia in a rat model of non-alcoholic steatohepatitis (NASH). Methods: The NASH rat model was generated by feeding the animals a high-sucrose, high-fat for diet for 12 weeks. We then measured alterations in levels of LPS, TNF alpha, IL-6, ALT, TG in plasma, and TNFa, and IL-6 in liver. We performed hematoxylin and eosin (HE) staining and immunohistochemical staining to document pathological changes. Expression of TLR4 and IRS-1 in liver was measured by Western Blot and RT-PCR. Results: Compared with control animals, levels of LPS, TNFa, IL-6 in plasma and the levels of TNFa, IL-6 in liver tissues gradually increased. Pathological changes and expression of TLR4 in liver were significantly increased compared with control. mRNA and protein levels of TLR4 and IRS-1 in livers were also upregulated. With concomitant treatment with glycine, endotoxin levels decreased, and TNFa and IL-6 levels in plasma and liver were significantly decreased compared to NASH rats. Pathological changes in liver and immunohistological expression of TLR4 in liver tissues were significantly improved compared to NASH rats. mRNA and protein levels of TLR4 were significantly downregulated while mRNA and protein levels of IRS-1 in liver were markedly upregulated. Progression of NASH appeared to be slowed or limited. Conclusion: These data suggest that hepatic TLR4 signaling pathway is activated in the NASH rat, and oral glycine may reduce the risk of endotoxemia and inflammation of the liver.