ABSTRACT
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide and macrophage polarization plays an important role in its pathogenesis. However, which molecule regulates macrophage polarization in NAFLD remains unclear. Herein, we showed NAFLD mice exhibited increased 17β-hydroxysteroid dehydrogenase type 7 (17β-HSD7) expression in hepatic macrophages concomitantly with elevated M1 polarization. Single-cell RNA sequencing on hepatic non-parenchymal cells isolated from wild-type littermates and macrophage-17β-HSD7 knockout mice fed with high fat diet (HFD) for 6 weeks revealed that lipid metabolism pathways were notably changed. Furthermore, 17β-HSD7 deficiency in macrophages attenuated HFD-induced hepatic steatosis, insulin resistance and liver injury. Mechanistically, 17β-HSD7 triggered NLRP3 inflammasome activation by increasing free cholesterol content, thereby promoting M1 polarization of macrophages and the secretion of pro-inflammatory cytokines. In addition, to help demonstrate that 17β-HSD7 is a potential drug target for NAFLD, fenretinide was screened out from an FDA-approved drug library based on its 17β-HSD7 dehydrogenase inhibitory activity. Fenretinide dose-dependently abrogated macrophage polarization and pro-inflammatory cytokines production, and subsequently inhibited fat deposition in hepatocytes co-cultured with macrophages. In conclusion, our findings suggest that blockade of 17β-HSD7 signaling by fenretinide would be a drug repurposing strategy for NAFLD treatment.
ABSTRACT
Objective@#To analyze the relationship between outdoor activity, screen time and 20 meter shuttle run test (20 m SRT) score among children and adolescents in Baoan District, Shenzhen, so as to provide scientific basis for the management and promotion of physical health of children and adolescents.@*Methods@#Stratified cluster sampling was used to select students from 14 schools in 6 communities in Baoan District of Shenzhen, from April to May 2019. A self designed questionnaire was used to investigate demographic characteristics, outdoor activity duration and screen time of primary and middle school students. A total of 3 192 primary and secondary school students in grade 1-12 were selected from each school. Weight, height and 20 m SRT were measured.@*Results@#About 985(30.9%) out of 3 192 primary and middle school students were estimated excellent on 20 m SRT test, with boys being higher than that of girls (34.7% vs 26.3%) ( χ 2=26.43, P <0.01). Logistic regression analysis showed that compared with the group with outdoor activity <2 h/d, the excellent and good performers on 20 m SRT with outdoor activity time ≥2 h/d was higher( OR=1.38, 95%CI =1.12-1.70). Compared with students with screen time ≥2 h/d, the excellent and good performers on 20 m SRT with screen time <2 h/d was higher( OR=1.42, 95%CI=1.17-1.71). Compared with students with outdoor activity time < 2 h/d and screen time ≥ 2 h/d, students with outdoor activity time ≥2 h/d and video time < 2 h/d had a higher proportion of excellent score on 20 m SRT( OR=1.97, 95%CI =1.46-2.67).@*Conclusion@#Increasing outdoor activity and reducing screen time are helpful to improve the performance score of 20 m SRT among primary and secondary school students.