Phase II enzyme induction by α-lipoic acid through phosphatidylinositol 3-kinase-dependent C/EBPs activation

Abstract

1. -Lipoic acid (-LA) activates antioxidant pathways and exerts insulin-like actions via phosphatidylinositol 3-kinase (PI3K), and previous studies from the authors' laboratory support the essential role of PI3K-dependent CCAAT/enhancer binding protein (C/EBP) activation in antioxidant defence responses. 2. The study investigated whether -LA treatment promoted phase II antioxidant gene induction through C/EBP activation and, if so, whether combined treatment of -LA and insulin synergistically increased target gene expression. 3. -LA treatment induced GSTA2 in H4IIE cells in a concentration-and time-dependent manner. In cells transfected with the regulatory region of the GSTA2 gene, -LA treatment increased luciferase reporter-gene activity. Immunoblot, immunocytochemistry, and gel shift assays identified the nuclear translocation and DNA binding of C/EBP and C/EBP, but not C/EBP, in -LA-treated cells.Deletion of the C/EBP binding site abolished the ability of -LA to promote the luciferase gene activity. 4. -LA, when combined with low concentrations of insulin, transactivated the GSTA2 gene to a greater extent compared with -LA or a higher concentration of insulin treatment alone. Combined treatment of -LA with insulin not only potentiated insulin signalling, but also enhanced PI3K-dependent activation of C/EBP and C/EBP forms. -LA in combination with insulin substantially increased haemoxygenase-1, microsomal epoxide hydrolase and -nicotinamide adenine dinucleotide phosphate (NADPH) quinone oxidoreductase expression, verifying the enhanced induction of other phase II enzymes. A dominant negative C/EBP transfection experiment indicated that GSTA2 gene induction by simultaneous treatment of -LA and insulin was also dependent on C/EBPs. 5. The results demonstrate that -LA induces phase II enzymes via PI3K-dependent C/EBP and C/EBP activation, and enhances the ability of insulin to promote target gene induction.

Sulforaphane and α-Lipoic Acid Upregulate the Expression of the π Class of Glutathione S-Transferase through c-Jun and Nrf2 Activation

“…Several in vivo studies have further provided evidence that LA supplementation decreases oxidative stress and restores reduced levels of other antioxidants under various physiologic and pathophysiologic conditions in brain and heart tissues and in RBC (51,52). In addition to acting as a coenzyme and antioxidant, recent work indicates that LA may also act as an inducer of several phase II detoxification enzymes, including GSTA and NQO1 through a CCAAT/enhancer binding protein and Nrf2-dependent pathway (8). In this study, we further showed that LA and DHLA activate AP-1 and Nrf2 translocation into the nucleus, where they bind to GPEI and upregulate GSTP transcription.…”

“…The accumulated evidence supports that garlic alliin-derived allyl sulfides and cruciferous isothiocyanates protect animals against a variety of chemical carcinogens (1,6). This chemoprevention can be partly explained by the potency of these phytochemicals in modulating the activity and gene expression of phase II detoxification enzymes (7)(8)(9).…”

“…In human leukemia HL-60 cells and neuroblastoma SH-SY5Y cells, LA is effective at upregulating NQO1 gene transcription (26,27). LA induction of GSTA2 expression is likely associated with the phosphatidylinositol 3-kinase pathway (8). Regarding GSTP, however, it is not clear whether LA and DHLA induce the expression of this detoxification enzyme.…”

Effect of dietary α-lipoic acid on the mRNA expression of genes involved in drug metabolism and antioxidation system in rat liver

“…Previous studies have indicated that α-lipoic acid increases the mRNA expression or the activity or protein levels of enzymes involved in drug metabolism, including NAD(P)H:quinone oxidoreductase ( 16 – 18 ) , Gst-α2 and microsomal epoxide hydrolase ( 18 ) , in various types of cultured cells. However, an animal study examining the physiological activity of α-lipoic acid affecting drug-metabolising enzymes has been lacking.…”

C/EBPβ and C/EBPδ transcription factors: Basic biology and roles in the CNS

“…There are reports showing significant levels of cytoplasmic C/EBPβ in hepatocyte cell lines (Ki and Kim 2008;Lee et al 2007;Yin et al 1996), in a colorectal cancer cell line (Chinery et al 1997) and in thyroid papillary carcinoma cells (Akagi et al 2008;Pomerance et al 2005). Phosphorylation of Ser239 in mouse (Ser288 human), which is part of the NLS, regulates C/EBPβ nuclear transport.…”