Dietary conjugated linoleic acid (CLA) is being investigated for beneficial effects for disease prevention and treatment in a variety of experimental models, including obesity and type 2 diabetes. To date, rodent studies suggest that trans-10,cis-12 (t10,c12) CLA is associated with greater insulin resistance, despite lower body fat, and that a CLA mixture (and perhaps c9,t11) could be beneficial for the management of insulin resistance. Studies investigating the mechanisms by which CLA operates at the cellular level show that the primary targets for CLA are members of the nuclear receptor family, particularly the lipostat transcription factors peroxisome proliferator-activated receptor alpha (PPARalpha), PPARgamma, sterol regulatory element-binding protein 1c, and liver X receptor alpha. Consequently, the effects of CLA on glucose metabolism are likely secondary effects mediated through factors such as PPARgamma coactivator 1 that are controlled by these nuclear receptors. The different responses of normal compared with insulin-resistant obese rodents suggest that interactions of CLA isomers with the cellular components that contribute to development of metabolic syndrome require further investigation.
Expression of the phosphoenolpyruvate carboxykinase (PEPCK) gene is induced by 3-aminobenzamide, an inhibitor of poly(ADP-ribose) polymerase. Synthesis of PEPCK mRNA is repressed by insulin, but remains detectable in H4IIE hepatoma cells exposed simultaneously to both 3-aminobenzamide and insulin. This capability of 3-aminobenzamide to block the inhibitory actions of insulin suggests that ADPribosylation is required for the regulation of PEPCK gene expression by insulin. Furthermore, neither changes in chromatin condensation nor cell growth status were linked to these events. The inability of 3,4-dihydro-5-methylisoquinolinone (PD128763), a selective inhibitor of poly(ADP-ribose) polymerase, to impede insulin-dependent repression of PEPCK gene expression, however, indicated that 3-aminobenzamide does not operate by inhibiting poly(ADP-ribosyl)ation. The potential involvement of mono(ADP-ribosyl)ation, a process that is also inhibited by 3-aminobenzamide, in the regulation of PEPCK gene activity was then evaluated. Analysis of poly(ADP-ribose) polymerase activity and poly-(ADP-ribosyl)ation confirmed that there were no significant changes in response to insulin, while microsomal mono(ADP-ribosyl)transferase activity was elevated approximately fourfold. An increase in protein hydroxylamine-sensitive mono(ADP-ribosyl)ation was observed following insulin treatment. The sensitivity of the mono(ADP-ribosyl)transferase activity to 3-aminobenzamide but not PD128763 makes it plausible that mono(ADP-ribosyl)ation rather than poly(ADP-ribosyl)ation contributes to the regulation of PEPCK gene expression.Keywords : phosphoenolpyruvate carboxykinase; ADP-ribosylation; 3-aminobenzamide; insulin.Expression of the hepatic phosphoenolpyruvate carboxyki-ments found at position Ϫ1150 and position Ϫ450 [5]. While it has been demonstrated that insulin operates through an insulinnase (PEPCK) gene is transcriptionally regulated by insulin and other humoral agents in response to changes in glucose utiliza-responsive element (IRE) site present at position Ϫ410 [6], neither the proteins that bind to this site nor details of the signalling tion [1, 2]. In the fasting state and under conditions of stress, blood glucose levels are elevated by an increase in PEPCK system that conveys signals from the insulin receptor have been identified. mRNA synthesis through the actions of glucagon and glucocorticoids. In contrast, high blood glucose levels stimulate the reThe repression of PEPCK gene expression by insulin in the lease of insulin, which represses gene activity. Molecular dissec-presence of positive mediators such as glucagon indicates that tion has demonstrated that each humoral agent operates through insulin is a dominant factor [7]. Since glucagon-dependent a distinct regulatory element present in the PEPCK gene pro-CREB phosphorylation is not prevented by insulin, transcripmoter [3]. Glucagon, for instance, functions through the cAMP-tional inactivation likely involves an IRE-binding protein (IRdependent phosphorylation of the cAMP-resp...
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