Hepatocellular carcinoma (HCC) is a highly vascularized solid tumor with a fast growth rate. According to bioinformatics analysis, CC chemokine ligand 23 (CCL23) has clinical significance for survival and prognosis in HCC. The online databases TCGA and CCLE were used to analyze the expression level of CCL23, and its expression was also measured in HCC cell lines by RT-qPCR and Western blotting. The STRING database and co-immunoprecipitation were employed to evaluate the association between CCL23 and transcription factor activating enhancer binding protein 4 (TFAP4). Overexpression plasmids for CCL23 (Ov-CCL23) and TFAP4 (Ov-TFAP4) were transfected into Huh-7 cells to detect TFAP4 expression. Huh-7 cells injected with OV-negative control (NC)/Ov-CCL23 or OV-NC/Ov-CCL23 plus Ov-TFAP4 were utilized to study the function of CCL23/TFAP4. Cell proliferation, invasion and human umbilical vein endothelial cell tube formation assays were conducted. The database revealed decreased expression of CCL23 in HCC and that it was commonly downregulated in HCC cell lines. TFAP4 expression was negatively correlated with CCL23. The overexpression of CCL23 inhibited the proliferation and invasion of Huh-7 cells, whereas TFAP4 blocked these effects. Similarly, the supernatant of CCL23-upregulated cells exhibited significantly lower tube formation potential, and low vascular endothelial growth factor A (VEGFA), VEGFRs expression compared with those of non-transfected Huh-7 cells, while TFAP4 plasmid co-transfected markedly increased these. Taken together, the present study suggests that CCL23 is expressed at low levels in HCC; it inhibits HCC cell proliferation, invasion and angiogenesis in vitro ; and its action is negatively associated with and can be blocked by TFAP4.
Fat deposition and lipid metabolism are closely related to the morphology, structure and function of mitochondria. The morphology of mitochondria between fusion and fission processes is mainly regulated by protein posttranslational modification (PTM). Intermittent fasting (IF) promotes high expression of Sirtuin 3 (Sirt3) and induces mitochondrial fusion in high-fat diet (HFD)-fed mice. However, the mechanism by which Sirt3 participates in mitochondrial protein acetylation during IF to regulate mitochondrial fusion and fission dynamics remains unclear. This article demonstrates that IF promotes mitochondrial fusion and improves mitochondrial function in HFD mouse inguinal white adipose tissue (iWAT). Proteomic sequencing revealed that IF increased protein deacetylation levels in HFD mice and significantly increased Sirt3 mRNA and protein expression. After transfecting with Sirt3 overexpression or interference vectors into adipocytes, we found that Sirt3 promoted adipocyte mitochondrial fusion and improved mitochondrial function. Furthermore, Sirt3 regulates the JNK-FIS1 pathway by deacetylating malate dehydrogenase 2 (MDH2) to promote mitochondrial fusion. In summary, our study indicates that IF promotes mitochondrial fusion and improves mitochondrial function by upregulating the high expression of Sirt3 in HFD mice, promoting deacetylation of MDH2, and inhibiting the JNK-FIS1 pathway. This research provides theoretical support for studies related to energy limitation and animal lipid metabolism.
BackgroundNonalcoholic fatty liver disease (NAFLD) is the main reason for cirrhosis and hepatocellular carcinoma. As a starting point for NAFLD, the treatment of nonalcoholic fatty liver (NAFL) is receiving increasing attention. Mice fed a high‐fat diet (HFD) and hereditary leptin deficiency (ob/ob) mice are important NAFL animal models. However, the comparison of these mouse models with human NAFL is still unclear.MethodsIn this study, HFD‐fed mice and ob/ob mice were used as NAFL animal models. Liver histopathological characteristics were compared, and liver transcriptome from both mouse models was performed using RNA sequencing (RNA‐seq). RNA‐seq data obtained from the livers of NAFL patients was downloaded from the GEO database. Global gene expression profiles in the livers were further analyzed using functional enrichment analysis and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway.ResultsOur results showed that the biochemical parameters of both mouse models and human NAFL were similar. Compared with HFD‐fed mice, ob/ob mice were more similar in histologic appearance to NAFL patients. The liver transcriptome characteristics partly overlapped in mice and humans. Furthermore, in the NAFL pathway, most genes showed similar trends in mice and humans, thus demonstrating that both types of mice can be used as models for basic research on NAFL, considering the differences.ConclusionOur findings show that HFD‐fed mice and ob/ob mice can mimic human NAFL partly in pathophysiological process. The comparative analysis of liver transcriptome profile in mouse models and human NAFL presented here provides insights into the molecular characteristics across these NAFL models.
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