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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.<\/jats:p>","DOI":"10.3390\/nu14183796","type":"journal-article","created":{"date-parts":[[2022,9,16]],"date-time":"2022-09-16T01:35:10Z","timestamp":1663292110000},"page":"3796","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Alanyl-Glutamine Protects Mice against Methionine- and Choline-Deficient-Diet-Induced Steatohepatitis and Fibrosis by Modulating Oxidative Stress and Inflammation"],"prefix":"10.3390","volume":"14","author":[{"given":"Jiaji","family":"Hu","sequence":"first","affiliation":[{"name":"Institute of Drug Discovery Technology, Ningbo University, Ningbo 315211, China"},{"name":"Ningbo Institute of Marine Medicine, Peking University, Ningbo 315010, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yigang","family":"Zheng","sequence":"additional","affiliation":[{"name":"Institute of Drug Discovery Technology, Ningbo University, Ningbo 315211, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hanglu","family":"Ying","sequence":"additional","affiliation":[{"name":"Institute of Drug Discovery Technology, Ningbo University, Ningbo 315211, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0581-4615","authenticated-orcid":false,"given":"Huabin","family":"Ma","sequence":"additional","affiliation":[{"name":"Institute of Drug Discovery Technology, Ningbo University, Ningbo 315211, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Long","family":"Li","sequence":"additional","affiliation":[{"name":"Institute of Drug Discovery Technology, Ningbo University, Ningbo 315211, China"},{"name":"State Key Laboratory of Chemical Oncogenomics, Tsinghua Shenzhen International Graduate School, Shenzhen 518055, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yufen","family":"Zhao","sequence":"additional","affiliation":[{"name":"Institute of Drug Discovery Technology, Ningbo University, Ningbo 315211, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,9,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"154797","DOI":"10.1016\/j.metabol.2021.154797","article-title":"A new mechanism of obeticholic acid on NASH treatment by inhibiting NLRP3 inflammasome activation in macrophage","volume":"120","author":"Huang","year":"2021","journal-title":"Metabolism"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"eabe1692","DOI":"10.1126\/scitranslmed.abe1692","article-title":"Hepatocyte TLR4 triggers inter-hepatocyte Jagged1\/Notch signaling to determine NASH-induced fibrosis","volume":"13","author":"Yu","year":"2021","journal-title":"Sci. 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