Agognon, Ayewa Lawoe (2024) Marine‑Derived Phosphoeleganin and Its Semisynthetic Derivative Decrease IL6 Levels and Improve Insulin Signalling in Human Hepatocellular Carcinoma Cells. [Tesi di dottorato]

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In recent decades, numerous compounds from botanical and marine organisms have been shown to be source of interest to the pharmaceutical industry such as potential antidiabetics and an alternative to current drugs, which often display heavy side-effects. Phosphoeleganin (PE), a polyketide purified from the Mediterranean ascidian Sidnyum elegans has shown promising antidiabetic effect. Thus, the objective of this study was to evaluate the effect of PE and its derivatives, PE/2 and PE/3, on insulin sensitivity in human hepatocellular carcinoma (HepG2) cells. In an initial stage, these molecules effect on the cells were studied in presence and absence of insulin. In a second stage, PE and PE2, which proved to affect insulin receptor (INSR) and AKT phosphorylation, were attested for their effect on phosphoenolpyruvate carboxykinase (PEPCK) expression and on glycogen production. Lastly, we evaluated the expression and secretion of diverse inflammatory molecules on HepG2 cells. In our experiments, insulin stimulates the phosphorylation of its receptor and AKT by 1.5- and 3.5-fold, respectively, whereas in the presence of PE, PE/2, and PE/3, the insulin-induced pINSR increases by 2.1-, 2-, and 1.5-fold and AKT phosphorylation by 7.1-, 6.0-, and 5.1-fold, respectively. Interestingly, PE and PE/2 have an additive effect on insulin-mediated reduction of phosphoenolpyruvate carboxykinase (PEPCK) expression. Furthermore, both compounds reduce glycogen synthesis although PE/2 exhibits a higher and more significant reduction than PE. Finally, PE and PE/2, but not PE/3, decrease interleukin 6 (IL6) secretion and expression before and after palmitic acid incubation, while in the presence of high glucose (HG), only PE reduces IL6. Levels of other cytokines are not significantly affected by PE and its derivates. All these data suggest that PE and its synthetic-derived compound, PE/2, significantly decrease IL6 and improve hepatic insulin signalling. As IL6 impairs insulin action, it could be hypothesized that PE and PE/2, by inhibiting IL6, may improve the hepatic insulin pathway.

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