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Research ArticleCELLULAR AND MOLECULAR

Identification of the Insulin Signaling Cascade in the Regulation of Alpha-Class Glutathione S-Transferase Expression in Primary Cultured Rat Hepatocytes

Sang K. Kim, Mohamed A. Abdelmegeed and Raymond F. Novak
Journal of Pharmacology and Experimental Therapeutics March 2006, 316 (3) 1255-1261; DOI: https://doi.org/10.1124/jpet.105.096065
Sang K. Kim
Institute of Environmental Health Sciences, Wayne State University, Detroit, Michigan
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Mohamed A. Abdelmegeed
Institute of Environmental Health Sciences, Wayne State University, Detroit, Michigan
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Raymond F. Novak
Institute of Environmental Health Sciences, Wayne State University, Detroit, Michigan
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Abstract

We reported previously that insulin elevated alpha-class glutathione S-transferase (GSTs) protein levels in primary cultured rat hepatocytes (Kim et al., 2003b). In contrast, glucagon down-regulated alpha- and pi-class GST expression, and mechanistic research implicated cAMP and protein kinase A in this process (Kim et al., 2003b). The present study examines the signaling pathways involved in the regulation of alpha-class GST in response to insulin in primary cultured rat hepatocytes. Protein levels of GSTA1/2 and GSTA3/5 and activity of GST toward 7-chloro-4-nitrobenzo-2-oxa-1,3-diazole (NBD) were increased in an insulin concentration-dependent manner. Treatment of cells with the phosphatidylinositol 3-kinase (PI3K) inhibitors wortmannin and LY294002 [2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one] or rapamycin, an inhibitor of mammalian target of rapamycin and ribosomal p70 S6 kinase (p70S6K) phosphorylation, or with an adenovirus containing green fluorescent protein and a dominant-negative and kinase-dead Akt, effectively inhibited the insulin-mediated increase in alpha-class GST expression and GST activity toward NBD. In contrast, PD98059 (2′-amino-3′-methoxyflavone), an inhibitor of mitogen-activated protein kinase kinase, SP600125 (1,9-pyrazoloanthrone), an inhibitor of c-Jun N-terminal kinase, SB203580 [4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imadazole], an inhibitor of p38 mitogen-activated protein kinase, or bisindolylmaleimide, a broad spectrum inhibitor of protein kinase C, did not inhibit the insulin-mediated increase in alpha-class GST protein levels in hepatocytes. These results show that PI3K/Akt/p70S6K signaling is active in the insulin-mediated up-regulation of the antioxidant defense system and that low insulin levels, as encountered in diabetes, potentially increase the susceptibility of hepatocytes to xenobiotic-mediated and/or oxidative stress-mediated damage.

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Journal of Pharmacology and Experimental Therapeutics: 316 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 316, Issue 3
1 Mar 2006
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Research ArticleCELLULAR AND MOLECULAR

Identification of the Insulin Signaling Cascade in the Regulation of Alpha-Class Glutathione S-Transferase Expression in Primary Cultured Rat Hepatocytes

Sang K. Kim, Mohamed A. Abdelmegeed and Raymond F. Novak
Journal of Pharmacology and Experimental Therapeutics March 1, 2006, 316 (3) 1255-1261; DOI: https://doi.org/10.1124/jpet.105.096065

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Research ArticleCELLULAR AND MOLECULAR

Identification of the Insulin Signaling Cascade in the Regulation of Alpha-Class Glutathione S-Transferase Expression in Primary Cultured Rat Hepatocytes

Sang K. Kim, Mohamed A. Abdelmegeed and Raymond F. Novak
Journal of Pharmacology and Experimental Therapeutics March 1, 2006, 316 (3) 1255-1261; DOI: https://doi.org/10.1124/jpet.105.096065
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