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Here, we explored the potential benefit of P7C3\u2010A20, a novel aminopropyl carbazole compound with neuroprotective activity, in a NAFLD model, induced in mice by a high\u2010fat diet (HFD).<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>C57BL\/6J mice were given a HFD (42% fat content) for 16 weeks to induce NAFLD. P7C3\u2010A20 (20 mg\u00b7kg<jats:sup>\u22121<\/jats:sup>\u00b7day<jats:sup>\u22121<\/jats:sup>) was given by gavage for 2 weeks. Indirect calorimetry, histological analysis, immunoblotting, immunohistochemistry, and biomedical examinations were performed. Gut microbiota were determined using a 16S ribosomal RNA sequencing analysis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>P7C3\u2010A20 treatment reduced body weight gain\/adiposity, improved insulin resistance, promoted energy expenditure (O<jats:sub>2<\/jats:sub> consumption\/CO<jats:sub>2<\/jats:sub> production), inhibited lipid oxidation, suppressed hepatic inflammation (Kupffer cell number and pro\u2010inflammatory factors), decreased necroptosis\/apoptosis (receptor\u2010interacting protein kinase 3, cleaved caspase\u20103, and TUNEL), and alleviated liver fibrosis and injury. Mechanistically, P7C3\u2010A20 stimulated FGF21 and FGF1 via activating liver kinase B1 (LKB1) and AMP\u2010activated protein kinase (AMPK), which further resulted in a reduced nuclear translocation of CREB\u2010regulated transcription coactivator 2 (CRTC2). In AMPK\u03b12 knockout mice, the protection of P7C3\u2010A20 against HFD\u2010induced metabolism abnormalities and fat accumulation, as well as the elevation of blood FGF21 and FGF1, was abolished. P7C3\u2010A20 increased the gut microbiota species richness. Moreover, it enhanced the proportions of <jats:italic>Akkermansia<\/jats:italic>, <jats:italic>Lactobacillus<\/jats:italic>, and Prevotellaceae, while reducing the proportions of Enterobacteriaceae, <jats:italic>Escherichia<\/jats:italic>, and <jats:italic>Parasutterella.<\/jats:italic><\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>P7C3\u2010A20 increased levels of NAD+ and alleviated NAFLD through stimulating FGF21 and FGF1 in an LKB1\/AMPK\/CRTC2\u2010dependent manner and shaping gut microbiota.<\/jats:p><\/jats:sec><jats:sec><jats:title>LINKED ARTICLES<\/jats:title><jats:p>This article is part of a themed issue on Cellular metabolism and diseases. To view the other articles in this section visit <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/bph.v178.10\/issuetoc\">http:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/bph.v178.10\/issuetoc<\/jats:ext-link><\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.15008","type":"journal-article","created":{"date-parts":[[2020,2,10]],"date-time":"2020-02-10T07:08:50Z","timestamp":1581318530000},"page":"2111-2130","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["P7C3\u2010A20 alleviates fatty liver by shaping gut microbiota and inducing FGF21\/FGF1, via the AMP\u2010activated protein kinase\/CREB regulated transcription coactivator 2 pathway"],"prefix":"10.1111","volume":"178","author":[{"given":"Xia","family":"Hua","sequence":"first","affiliation":[{"name":"Department of Pharmacology, School of Pharmacy Second Military Medical University\/Naval Medical University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Di\u2010Yang","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Pharmacy Second Military Medical University\/Naval Medical University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen\u2010Jie","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Pharmacy Second Military Medical University\/Naval Medical University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiang\u2010Tao","family":"Fu","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Pharmacy Second Military Medical University\/Naval Medical University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Tong","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Shanghai Tenth People's Hospital affiliated to School of Medicine, Tongji University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Si\u2010Jia","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Shanghai Tenth People's Hospital affiliated to School of Medicine, Tongji University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei\u2010Yan","family":"Zeng","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Shanghai Tenth People's Hospital affiliated to School of Medicine, Tongji University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shen\u2010Xi","family":"Ouyang","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Shanghai Tenth People's Hospital affiliated to School of Medicine, Tongji University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guo\u2010Yan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Shanghai Tenth People's Hospital affiliated to School of Medicine, Tongji University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shu\u2010Na","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Pharmacy Second Military Medical University\/Naval Medical University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong\u2010Jie","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Shanghai Tenth People's Hospital affiliated to School of Medicine, Tongji University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao\u2010Yu","family":"Miao","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Pharmacy Second Military Medical University\/Naval Medical University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1650-3353","authenticated-orcid":false,"given":"Pei","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Pharmacy Second Military Medical University\/Naval Medical University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,3,24]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.14750"},{"issue":"1","key":"e_1_2_11_3_1","first-page":"S297","article-title":"The Concise Guide to PHARMACOLOGY 2019\/20: Enzymes","volume":"176","author":"Alexander S. 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