α-Lipoic Acid as a Directly Binding Activator of the Insulin Receptor: Protection from Hepatocyte Apoptosis†

Background and aim:  α-Lipoic acid has cytoprotective potential which has previously been explained by its antioxidant properties. The aim of this study was to assess LA-induced-specific cytoprotective signalling pathways in hepatocytes. Methods:  Apoptosis of rat hepatocytes was induced by actinomycinD/TNF-α. Caspase-3-like activity was determined by a fluorometric; LDH by an enzymatic assay; and phosphorylation of the insulin receptor, Akt, and Bad by Western blot (after immunoprecipitation). Protein kinase and insulin receptor activities were measured by in vitro phosphorylation. Computer modeling studies were performed by using the program GRID. Results:  α-Lipoic acid decreased actinomycinD/TNF-α-induced apoptosis, as did the antioxidants Trolox and N-acetylcysteine. The activation of PI3-kinase/Akt involving phosphorlyation of Bad markedly contributed to the cytoprotective action of α-lipoic acid. α-Lipoic acid but not other antioxidants protected against actinomycinD/TNF-α-induced apoptosis via pho...