P7C3-A20 alleviates fatty liver by shaping gut microbiota and inducing FGF21/FGF1, via the AMP-activated protein kinase/CREB regulated transcription coactivator 2 pathway

Background and Purpose Non-alcoholic fatty liver disease (NAFLD) is a worldwide public health problem with no established pharmacological therapy. Here, we explored the potential benefit of P7C3-A20, a novel aminopropyl carbazole compound with neuroprotective activity, in a NAFLD model, induced in mice by a high-fat diet (HFD). Experimental Approach C57BL/6J mice were given a HFD (42% fat content) for 16 weeks to induce NAFLD. P7C3-A20 (20 mg center dot kg(-1)center dot day(-1)) 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. Key Results P7C3-A20 treatment reduced body weight gain/adiposity, improved insulin resistance, promoted energy expenditure (O(2)consumption/CO(2)production), inhibited lipid oxidation, suppressed hepatic inflammation (Kupffer cell number and pro-inflammatory factors), decreased necroptosis/apoptosis (receptor-interacting protein kinase 3, cleaved caspase-3, and TUNEL), and alleviated liver fibrosis and injury. Mechanistically, P7C3-A20 stimulated FGF21 and FGF1 via activating liver kinase B1 (LKB1) and AMP-activated protein kinase (AMPK), which further resulted in a reduced nuclear translocation of CREB-regulated transcription coactivator 2 (CRTC2). In AMPK alpha 2 knockout mice, the protection of P7C3-A20 against HFD-induced metabolism abnormalities and fat accumulation, as well as the elevation of blood FGF21 and FGF1, was abolished. P7C3-A20 increased the gut microbiota species richness. Moreover, it enhanced the proportions ofAkkermansia,Lactobacillus, and Prevotellaceae, while reducing the proportions of Enterobacteriaceae,Escherichia, andParasutterella. Conclusions and Implications P7C3-A20 increased levels of NAD+ and alleviated NAFLD through stimulating FGF21 and FGF1 in an LKB1/AMPK/CRTC2-dependent manner and shaping gut microbiota.

Automated summary

P7C3-A20 can alleviate NAFLD by stimulating FGF21 and FGF1, promoting gut microbiota balance, and reducing metabolic abnormalities and inflammation.