The aim of the study was to elucidate the mechanism by which advanced glycation end products (AGEs) promote cell proliferation in liver cancer cells.We treated liver cancer HepG2 cells with 200 mg/L AGEs or bovine serum albumin (BSA) and assayed for cell viability, cell cycle, and apoptosis. We performed real-time PCR and Western blot analysis for RNA and protein levels of carbohydrate responsive element-binding protein (ChREBP) in AGEs- or BSA-treated HepG2 cells. We analyzed the level of reactive oxygen species (ROS) in HepG2 cells treated with AGEs or BSA.We found that increased S-phase cell percentage and decreased apoptosis contributed to AGEs-induced liver cancer cell proliferation. Real-time PCR and Western blot analysis showed that AGEs stimulated RNA and protein levels of ChREBP, a transcription factor promoting glycolysis and maintaining cell proliferation in liver cancer cells. Intriguingly, the level of ROS was higher in AGEs-treated liver cancer cells. Treating liver cancer cells with antioxidant N-acetyl cystein (NAC) partly blocked AGEs-induced ChREBP expression and cell proliferation.Our results suggest that the AGEs-ROS-ChREBP pathway plays a critical role in promoting ChREBP expression and liver cancer cell proliferation.
The prevalence of diabetes mellitus has been increasing for decades worldwide. To develop safe and potent therapeutics, animal models contribute a lot to the studies of the mechanisms underlying its pathogenesis. Dietary induction using is a well-accepted protocol in generating insulin resistance and diabetes models. In the present study, we reported the multi-omics profiling of the liver and sera from both peripheral blood and hepatic portal vein blood from Macaca fascicularis that spontaneously developed Type-2 diabetes mellitus with a chow diet (sDM). The other two groups of the monkeys fed with chow diet and high-fat high-sugar (HFHS) diet, respectively, were included for comparison. Analyses of various omics datasets revealed the alterations of high consistency. Between the sDM and HFHS monkeys, both the similar and unique alterations in the lipid metabolism have been demonstrated from metabolomic, transcriptomic, and proteomic data repeatedly. The comparison of the proteome and transcriptome confirmed the involvement of fatty acid binding protein 4 (FABP4) in the diet-induced pathogenesis of diabetes in macaques. Furthermore, the commonly changed genes between spontaneous diabetes and HFHS diet-induced prediabetes suggested that the alterations in the intra- and extracellular structural proteins and cell migration in the liver might mediate the HFHS diet induction of diabetes mellitus.
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