Alanyl-Glutamine Protects Mice against Methionine- and Choline-Deficient-Diet-Induced Steatohepatitis and Fibrosis by Modulating Oxidative Stress and Inflammation

Abstract

Nonalcoholic steatohepatitis (NASH) is a common chronic liver disease with increasing prevalence rates over years and is associated with hepatic lipid accumulation, liver injury, oxidative stress, hepatic inflammation, and liver fibrosis and lack of approved pharmacological therapy. Alanyl-glutamine (Ala-Gln) is a recognized gut-trophic nutrient that has multiple pharmacological effects in the prevention of inflammation- and oxidative-stress-associated diseases. Nevertheless, whether Ala-Gln has a protective effect on NASH still lacks evidence. The aim of this study is to explore the influence of Ala-Gln on NASH and its underlying mechanisms. Here, C57BL/6 mice were fed a methionine- and choline-deficient (MCD) diet to establish the model of NASH, and Ala-Gln at doses of 500 and 1500 mg/kg were intraperitoneally administered to mice along with a MCD diet. The results showed that Ala-Gln treatment significantly attenuated MCD-induced hepatic pathological changes, lowered NAFLD activity score, and reduced plasma alanine transaminase (ALT), aspartate transaminase (AST) and lactate dehydrogenase (LDH) levels. Ala-Gln dramatically alleviated lipid accumulation in liver through modulating the expression levels of fatty acid translocase (FAT/CD36) and farnesoid X receptor (FXR). In addition, Ala-Gln exerted an anti-oxidant effect by elevating the activities of superoxide dismutase (SOD) and glutathione peroxidase (GPX). Moreover, Ala-Gln exhibited an anti-inflammatory effect via decreasing the accumulation of activated macrophages and suppressing the production of proinflammatory mediators. Notably, Ala-Gln suppressed the development of liver fibrosis in MCD-diet-fed mice, which may be due to the inhibition of hepatic stellate cells activation. In conclusion, these findings revealed that Ala-Gln prevents the progression of NASH through the modulation of oxidative stress and inflammation and provided the proof that Ala-Gln might be an effective pharmacological agent to treat NASH.

Risk factors for liver fibrosis progression from early stage to late stage in nonalcoholic fatty liver disease: a systematic review and meta-analysis

“…Published by Francis Academic Press, UK -43-liver fibrosis is reflected in increased levels of aspartate aminotransferase. It has been shown that alanylglutamine treatment significantly attenuates methionine-and choline-induced liver pathological changes reduces aspartate aminotransferase levels, decreases liver inflammation and collagen deposition in liver fibrosis, promotes recovery from hepatocellular injury, and thus inhibits the progression of liver fibrosis [33,34]. The above studies have shown to some extent that high levels of aspartate aminotransferase are predictive of liver In addition, meta-analysis showed that aspartate aminotransferase increased with the severity of fibrosis in advanced NAFLD [35] .…”

Alanyl-Glutamine Dipeptide Attenuates Non-Alcoholic Fatty Liver Disease Induced by a High-Fat Diet in Mice by Improving Gut Microbiota Dysbiosis

“…AG was obtained as previously reported [ 16 ]. The standard diet (SD) and HFD (60 kcal%) was obtained from Research Diets Inc. (New Brunswick, NJ, USA).…”

“…Moreover, AG has been found to have beneficial effects on liver function, including hepatoprotection and the attenuation of liver injury induced by oxidative stress, making it a promising therapeutic agent for various liver diseases [ 14 , 15 ]. We have reported the therapeutic potential of AG in methionine- and choline-deficient (MCD) diet-triggered NASH [ 16 ]. However, the MCD diet-treated mice are lean mice which could reflect the pathological features of obesity-related NAFLD; whether AG could affect HFD-induced obesity-related NAFLD still needs to be studied further.…”

Glutamine‐derived peptides: Current progress and future directions

“…Since 1995, Ala‐Gln has been approved as a parenteral nutrition drug for clinical treatment and its primary functions include maintaining gut health, enhancing immune function, providing nutritional support, and promoting metabolic health. In terms of intestinal health, Ala‐Gln helps maintain intestinal mucosal integrity, prevents intestinal leakage, and may improve intestinal function by inhibiting inflammatory responses (Hu, Zheng, et al., 2022; Liu, Zong, et al., 2023; Xing et al., 2017; Zou et al., 2019). In addition, Ala‐Gln has a positive effect on the immune system by increasing lymphocyte activity and enhancing the body's antiviral and antibacterial capabilities (Hou, Pai, et al., 2013).…”