Oral Glutamine Supplementation Protects Female Mice from Nonalcoholic Steatohepatitis

Abstract

Background: Genetic factors, a diet rich in fat and sugar, and an impaired intestinal barrier function are critical in the development of nonalcoholic steatohepatitis (NASH). The nonessential amino acid glutamine (Gln) has been suggested to have protective effects on intestinal barrier function but also against the development of liver diseases of various etiologies.

Objective: The effect of oral Gln supplementation on the development of Western-style diet (WSD)-induced NASH in mice was assessed.

Methods: Female 6- to 8-wk-old C57BL/6J mice were pair-fed a control (C) diet or a WSD alone or supplemented with 2.1 g l-Gln/kg body weight for 6 wk (C+Gln or WSD+Gln). Indexes of liver damage, lipid peroxidation, and glucose metabolism and endotoxin concentrations were measured.

Results: Although Gln supplementation had no effect on the loss of the tight junction protein occludin, the increased portal endotoxin and fasting glucose concentrations found in WSD-fed mice, markers of liver damage (e.g., nonalcoholic fatty liver disease activity score and number of neutrophils in the liver) were significantly lower in the WSD+Gln group than in the WSD group (~47% and ~60% less, respectively; P < 0.05). Concentrations of inducible nitric oxide synthase (iNOS) protein and 3-nitrotyrosin protein adducts were significantly higher in livers of WSD-fed mice than in all other groups (~8.6- and ~1.9-fold higher, respectively, compared with the C group; P < 0.05) but did not differ between WSD+Gln-, C-, and C+Gln-fed mice. Hepatic tumor necrosis factor α and plasminogen activator inhibitor 1 concentrations were significantly higher in WSD-fed mice (~1.6- and ~1.8-fold higher, respectively; P < 0.05) but not in WSD+Gln-fed mice compared with C mice.

Conclusion: Our data suggest that the protective effects of oral Gln supplementation on the development of WSD-induced NASH in mice are associated with protection against the induction of iNOS and lipid peroxidation in the liver.

Keywords: glutamine; hepatic inflammation; iNOS; nonalcoholic steatohepatitis; reactive oxygen species.