In:
British Journal of Pharmacology, Wiley, Vol. 178, No. 10 ( 2021-05), p. 2111-2130
Kurzfassung:
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·kg −1 ·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 AMPKα2 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 of Akkermansia , Lactobacillus , and Prevotellaceae, while reducing the proportions of Enterobacteriaceae, Escherichia , and Parasutterella. 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. LINKED ARTICLES This article is part of a themed issue on Cellular metabolism and diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.10/issuetoc
Materialart:
Online-Ressource
ISSN:
0007-1188
,
1476-5381
Sprache:
Englisch
Verlag:
Wiley
Publikationsdatum:
2021
ZDB Id:
2029728-2
SSG:
15,3
