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Alanyl-glutamine (AG), a dipeptide comprising alanine and glutamine, is commonly employed as a nutritional supplement in clinical settings. This research aims to evaluate the impact of AG on NAFLD triggered by a high-fat diet (HFD), while concurrently delving into the potential mechanisms underlying its effects. The results presented herein demonstrate a notable reduction in the elevated body weight, liver mass, and liver index induced by a HFD upon AG administration. These alterations coincide with the amelioration of liver injury and the attenuation of hepatic histological advancement. Furthermore, AG treatment manifests a discernible diminution in oil-red-O-stained regions and triglyceride (TG) levels within the liver. Noteworthy alterations encompass lowered plasma total cholesterol (TC) and low-density lipoprotein cholesterol (LDLC) concentrations, coupled with elevated high-density lipoprotein cholesterol (HDLC) concentrations. The mitigation of hepatic lipid accumulation resultant from AG administration is aligned with the downregulation of ACC1, SCD1, PPAR-\u03b3, and CD36 expression, in conjunction with the upregulation of FXR and SHP expression. Concomitantly, AG administration leads to a reduction in the accumulation of F4\/80-positive macrophages within the liver, likely attributable to the downregulated expression of MCP-1. Furthermore, AG treatment yields a decline in hepatic MDA levels and a concurrent increase in the activities of SOD and GPX. A pivotal observation underscores the effect of AG in rectifying the imbalance of gut microbiota in HFD-fed mice. Consequently, this study sheds light on the protective attributes of AG against HFD-induced NAFLD through the modulation of gut microbiota composition.<\/jats:p>","DOI":"10.3390\/nu15183988","type":"journal-article","created":{"date-parts":[[2023,9,15]],"date-time":"2023-09-15T03:50:10Z","timestamp":1694749810000},"page":"3988","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Alanyl-Glutamine Dipeptide Attenuates Non-Alcoholic Fatty Liver Disease Induced by a High-Fat Diet in Mice by Improving Gut Microbiota Dysbiosis"],"prefix":"10.3390","volume":"15","author":[{"given":"Yigang","family":"Zheng","sequence":"first","affiliation":[{"name":"Institute of Drug Discovery Technology, Ningbo University, Ningbo 315211, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanglu","family":"Ying","sequence":"additional","affiliation":[{"name":"Institute of Drug Discovery Technology, Ningbo University, Ningbo 315211, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiayi","family":"Shi","sequence":"additional","affiliation":[{"name":"Institute of Drug Discovery Technology, Ningbo University, Ningbo 315211, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Long","family":"Li","sequence":"additional","affiliation":[{"name":"Institute of Drug Discovery Technology, Ningbo University, Ningbo 315211, China"},{"name":"Qian Xuesen Collaborative Research Center of Astrochemistry and Space Life Sciences, Ningbo University, Ningbo 315211, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yufen","family":"Zhao","sequence":"additional","affiliation":[{"name":"Institute of Drug Discovery Technology, Ningbo University, Ningbo 315211, China"},{"name":"Qian Xuesen Collaborative Research Center of Astrochemistry and Space Life Sciences, Ningbo University, Ningbo 315211, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,9,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1038\/s41575-020-00406-0","article-title":"Nonalcoholic fatty liver disease: Another leap forward","volume":"18","author":"Abdelmalek","year":"2021","journal-title":"Nat. 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