Perilipin 5 regulates hepatic stellate cell activation and high-fat diet-induced non-alcoholic fatty liver disease.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases globally. Hepatic stellate cells (HSCs) are the major effector cells of liver fibrosis. HSCs contain abundant lipid droplets (LDs) in their cytoplasm during quiescence. Perilipin 5 (PLIN 5) is a LD surface-associated protein that plays a crucial role in lipid homeostasis. However, little is known about the role of PLIN 5 in HSC activation. METHODS: PLIN 5 was overexpressed in HSCs of Sprague-Dawley rats by lentivirus transfection. At the same time, PLIN 5 gene knockout mice were constructed and fed with a high-fat diet (HFD) for 20 weeks to study the role of PLIN 5 in NAFLD. The corresponding reagent kits were used to measure TG, GSH, Caspase 3 activity, ATP level, and mitochondrial DNA copy number. Metabolomic analysis of mice liver tissue metabolism was performed based on UPLC-MS/MS. AMPK, mitochondrial function, cell proliferation, and apoptosis-related genes and proteins were detected by western blotting and qPCR. RESULTS: Overexpression of PLIN 5 in activated HSCs led to a decrease in ATP levels in mitochondria, inhibition of cell proliferation, and a significant increase in cell apoptosis through AMPK activation. In addition, compared with the HFD-fed C57BL/6J mice, PLIN 5 knockout mice fed with HFD showed reduced liver fat deposition, decreased LD abundance and size, and reduced liver fibrosis. CONCLUSION: These findings highlight the unique regulatory role of PLIN 5 in HSCs and the role of PLIN 5 in the fibrosis process of NAFLD.

Role of Plin5 Deficiency in Progression of Non-Alcoholic Fatty Liver Disease Induced by a High-Fat Diet in Mice.

Characterized by steatosis, inflammation and fibrosis, non-alcoholic fatty liver disease (NAFLD) is a metabolic disorder. As a major lipid droplet-binding protein, Plin5 has been reported to have multiple effects on metabolism, but the effect of Plin5 deficiency on NAFLD is unknown. Plin5 knockout mice and wild-type mice were used to investigate the role of Plin5 in the progression of NAFLD by feeding a high-fat diet (HFD) for 20 weeks. Plin5 deficiency improved obesity induced by the HFD and altered glucose tolerance. Histological examination revealed that Plin5 deficiency alleviated hepatic steatosis and fibrosis induced by the HFD. Plin5 deficiency was also associated with a significant change in lipid metabolism-associated molecules. Further studies of these molecules indicated that Plin5 deficiency activated the expression of AMP-activated protein kinase and inhibited the core regulator of lipogenesis, sterol regulatory element binding protein 1 and its downstream lipid synthesis-related genes. These findings suggest that Plin5 deficiency ameliorates NAFLD by regulating lipid metabolism and inhibiting lipogenesis, and may provide a new strategy for the treatment of NAFLD.

Development and Validation of a Five-RNA-Based Signature and Identification of Candidate Drugs for Neuroblastoma.

Neuroblastoma (NBL) originating from the sympathetic nervous system is the most prevalent solid tumor in infancy. Although there is sufficient variability in prognosis among different age pyramids, age-related gene expression profiles and biomarkers remain poorly explored. The present study aimed to construct a signature based on differentially expressed genes (DEGs) between two age groups in NBL. Univariate Cox regression, multivariate Cox regression, and LASSO analyses were used to identify the optimal prognostic factors. The prediction ability of the model was assessed using the receiver operating characteristic (ROC) curve and C-index. Functional enrichment analysis was performed using the Kyoto Encyclopedia of Genes and Genomes and gene ontology databases. A total of 1,160 DEGs were identified between the two groups, and 204 DEGs impacted the survival of NBL. Functional enrichment analysis revealed that the DEGs were involved in retinol metabolism, cholesterol metabolism, and glycolysis/gluconeogenesis pathways. Five RNAs, namely F8A3, PDF, ANKRD24, FAXDC2, and TMEM160 were recruited into the signature. They were correlated with COG risk classification, INSS stage, and histology. MYCN amplification was linked to FAXDC2, TMEM160, PDF, and F8A3. The expression levels of ANKRD24, PDF, and TMEM160 were lower in the hyperdiploid groups. Only FAXDC2 levels were different in the different MKI grades. The ROC curve showed that the five-RNA-based signatures effectively predicted the OS of NBL (3-years AUC = 0.791, 5-years AUC = 0.816) in the TARGET cohort. The predictive capability was also validated by the GSE49711 cohort (3-years AUC = 0.851, 5-years AUC = 0.848). The C-index in the TARGET and GSE49711 cohorts was 0.749 and 0.809, respectively. The potential mechanisms of the five RNAs were also explored via gene set enrichment analysis, and candidate drugs targeting the five genes, including dabrafenib, vemurafenib, and bafetinib, were screened. In conclusion, we constructed a five-RNA-based signature to predict the survival of NBL and screened candidate agents against NBL.