Regulation of hepatic glucose production − Rakyat Biologi

Recent results from various animal models confirm the physiological importance of hepatic AMPK for whole-body glucose homeostasis. It has been first shown that systemic infusion of AICAR in normal and insulin-resistant obese rats leads to the inhibition of hepatic glucose production (HGP) (Bergeron et al., 2001). Then, several studies reported that AICAR treatment improve blood glucose levels and glucose tolerance in animal models of type 2 diabetes. However, the relative roles played by skeletal muscle and liver in mediating the hypoglycemic effect of AICAR remain unclear. In muscle-specific AMPK dominant-negative mice, AICAR has a weaker hypoglycemic effect than in control animals (Mu et al., 2001), suggesting that this compound lowers glycemia at least partly by increasing muscle glucose uptake. We demonstrated that AMPKa1a2_LS-/- mice display an impaired hypoglycemic response to AICAR, indicating that the liver as well participate to the hypoglycemic effect of AICAR (Figure 2). It has been also reported that short-term hepatic expression of AMPK-CA leads to mild hypoglycemia in normal mice (Foretz et al., 2005, Viana et al., 2006) and abolishes hyperglycemia in diabetic ob/ob and STZ-induced diabetic mice (Foretz et al., 2005). The hypoglycemic effect of AMPK activation is consistent with the abolition of HGP, as suggested by the down-regulation of gluconeogenic gene expression (e.g., phosphoenolpyruvate carboxykinase [PEPCK] and glucose-6-phosphatase [G6Pase]) and inhibition of glucose production in hepatic cells expressing AMPK-CA or treated with AICAR (Lochhead et al., 2000, Foretz et al., 2005, Viana et al., 2006). Using transcriptional profiling of hepatocyte cell lines treated with AICAR, the dual specificity phosphatase Dusp4 and the immediate early transcription factor Egr1 have been identified as transcriptional targets of AMPK that are necessary for its ability to fully repress glucose production (Berasi et al., 2006). Egr1 and Dusp4 act sequentially to mediate the inhibitory effect of AMPK on hepatic gluconeogenesis: increase in Egr1 protein is accompanied with increased binding to the Dusp4 promoter leading to Dusp4 expression and inhibition of PEPCK and G6Pase gene transcription (Berasi et al., 2006).

The importance of AMPK in the control of glucose output by the liver was recently highlighted by the potent effects of circulating adipocyte-derived hormones on whole-body glucose metabolism. A physiological link has been established between circulating resistin levels and hepatic AMPK activity in the maintenance of blood glucose (Banerjee et al., 2004). Low blood glucose levels and reduced HGP in mice lacking resistin are likely related, at least in part, to activation of AMPK and decreased expression of gluconeogenic enzymes in the liver. Interestingly, adiponectin signaling opposes that of resistin in the control of glucose homeostasis and activation of AMPK is though to underlie the ability of this adipocyte hormone to reduce HGP (Yamauchi et al., 2002). According to this result, adiponectin failed to regulate HGP in liver-specific AMPKa2 KO mice (Andreelli et al., 2006). AdipoR1 and AdipoR2 serve as adiponectin receptors and functional differences in adiponectin-signaling pathways in the liver have been recently demonstrated with AdipoR1 being tightly linked to activation of AMPK pathways whereas AdipoR2 being more associated with the activation of peroxisome proliferator-activated receptor-a (PPAR-a) pathways (Yamauchi et al., 2007, Bjursell et al., 2007).

Recently, the transcriptional co-activator transducer of regulated CREB activity 2 (TORC2) has been identified as a pivotal component of the gluconeogenic program (Koo et al., 2005). TORC2 mediates CREB-dependent transcription of PGC1a and its subsequent gluconeogenic targets PEPCK and G6Pase. TORC2 is regulated by multiple signaling pathways in response to changes in glucagon and insulin levels or intracellular energy status. Phosphorylation on Ser171 confers binding of the protein 14-3-3 and sequestration of TORC2 out of the nucleus, resulting in inhibition of gluconeogenic gene expression. The kinase responsible for phosphorylating Ser171 of TORC2 was initially identified as salt-inducible kinase 2 (SIK2), an AMPK-related protein kinase (Screaton et al., 2004). Recently, activation of AMPK was also found to phosphorylate TORC2 and regulate cytoplasmic translocation of TORC2 in primary hepatocyte cultures (Koo et al., 2005). Interestingly, in the absence of LKB1 in the liver, the expression of some of the key gluconeogenic genes are enhanced and the antidiabetic drug metformin no longer reduced blood glucose levels, demonstrating that hepatic LKB1/AMPK axis is required to maintain blood glucose levels (Shaw et al., 2005). LKB1 phosphorylates and activates a number of kinases including AMPK and SIK family members (Lizcano et al., 2004), suggesting that genetic deletion of LKB1 in liver will result in the loss of multiple metabolic checkpoints in the regulation of TORC2. In LKB1-deficient liver, AMPK was almost completely inactive, TORC2 was predominantly nuclear and fasting blood glucose levels were highly increased concomitantly with PEPCK and G6Pase gene expression (Shaw et al., 2005). The reduction of TORC2 protein levels by injection of adenoviruses bearing small hairpin RNA for TORC2 in mice lacking LKB1 in the liver resulted in decreased PGC-1a protein levels accompanied by a significant decrease in fasting blood glucose levels, suggesting that TORC2 is a critical downstream target of LKB1-dependent kinases in the control of gluconeogenesis (Shaw et al., 2005). In addition, a recent study has shown that metformin regulates hepatic gluconeogenesis through AMPK-dependent regulation of the orphan nuclear receptor small heterodimer partner (SHP) (Kim et al., 2008). AMPK activation caused upregulation of SHP gene expression and this in turn, inhibits PEPCK and G6Pase gene expression. It has been proposed that metformin could regulate the expression of hepatic gluconeogenic genes via both a short-term pathways, involving the protein stabilization or phosphorylation of AMPK-targeted transcription factors and coactivators, such as TORC2 (Shaw et al., 2005), HNF4a (Leclerc et al., 2001, Hong et al., 2003) and FoxO1 (Barthel et al., 2002) and a long-term effect exerted via the induction of SHP gene expression (Kim et al., 2008) (Figure 3). Lastly, it should be noted that AMPK has been also involved in the repression of gluconeogenic genes in response to ECGC treatment via a LKB1-independent pathway relying on CaMKK activation through production of ROS (Collins et al., 2007).