Action of melatonin on the regulation of PEPCK in human hepatocytes (HepG2)

Abstract

The metabolic changes involved absorptive period are linked to energy supply and accumulation of essential nutrients for maintaining energy homeostasis. These processes are orchestrated by insulin, a hormone produced and released by pancreatic beta cells. In patients with type II diabetes mellitus (T2DM) there is a decrease in insulin sensitivity, and consequently, all this adjustment for the depletion of plasma glucose is impaired. A common characteristic of this pathology is related to elevate fasting glucose levels in the morning. According Radziuk and Pye (2006) this primarily arises occurs due to increased endogenous glucose production by mechanisms related to the stimulation of gluconeogenesis and, probably, has a circadian regulation. It is known that regulating the expression of genes encoding enzymes of gluconeogenesis, such as glucose 6-phosphatase (G6Pase) and phosphoenol pyruvate carboxykinase (PEPCK), plays an important role in glucose homeostasis, and insulin inhibited this process. It is also consensus that the overexpression of these genes may contribute to the development of T2DM. Some studies have reported that the signal transducer and activator of transcription 3 (STAT3) plays as a key in the regulation of expression of these genes. However, the mechanisms of action of this transcription factor is still unclear. In this context, the STAT is a repressor of transcription of PEPCK and G6Pase (Wang et al. 2012, Kimura et al. 2012, Nie et al. 2009). In recent work, Ramadoss et al. (2009) demonstrated that phosphorylation of STAT3 is connected to the repression of expression of G6Pase, through the action of interleukin 6 (IL-6) in both HepG2 and in rat liver. Using immunoprecipitation of chromatin in vivo, this same study demonstrated that STAT3 binds to the promoter regions G6Pase and PEPCK, regulating negatively the expression of these genes. Nogueira et al. (2011) demonstrated that pinealectomized rats showed hepatic insulin resistance in nocturnal period, characterized by decreased phosphorylation of AKT and increased expression of PEPCK. Moreover, the pinealectomized rats showed an increase in conversion of pyruvate to glucose in the late evening, showing strong correlation between the absence of melatonin and related mechanisms to hepatic glucose output (Walnut et al., 2011). Added to this recently was demonstrated that melatonin may induce a rapid activation of STAT3 in Jurkat T cells (Lau et al. 2012). However, it is not known whether melatonin directly regulates the expression of PEPCK in hepatocytes and whether this fact is dependent on phosphorylation of STAT3. (AU)