Galactosamine is known to induce hepatic injury in rats that is similar in pathophysiology to viral hepatitis and drug-induced hepatitis in humans.60) Green tea has been shown to suppress galactosamine-induced liver injury in rats61,62) and one of the active components was identified as glycosidic flavonoids.62) In our study, intraperitoneal injection of galactosamine (500 mg/kg) induced liver injury with necrosis in rats and the oral administration of green tea rich in catechins inhibited the galactosamine’s action. Green tea restored levels of several biomarkers in galactosamine-treated rats to near control values.63) These biomarkers included serum transaminase activities, serum concentrations of tumor necrosis factor-α (TNF-α) and interleukin 1-β, and the hepatic mRNA expression of these inflammatory cytokines. The serum concentration in green tea-treated rats was about 55% of rats untreated after galactosamine injection. Since apoptosis of liver cells is involved in galactosamine-induced liver injury64) and TNF-α induces apoptosis,65) modulation of TNF-α appears to be a key action of EGCG (Fig. (Fig.44).
Hepatic ischemia-reperfusion activates Kupffer cells and initiates severe oxidative stress with enhanced production of reactive oxygen species (ROS) and TNF-α. Giakoustidis et al.66) reported the hepatoprotective effect of EGCG in rats by inhibiting apoptosis through attenuation of the expression of NF-κB, c-Jun, and caspase-3 in an experimental model of severe hepatic ischemia-reperfusion. Similarly, Okabe et al.65) demonstrated that green tea catechins induced growth inhibition and apoptosis by reducing TNF-α gene expression and TNF-α release, using the human stomach cancer cell line KATO III (Fig. (Fig.4).4). The EGCG’s action to suppress TNF-α expression may also have beneficial effect on diabetes, since TNF-α is involved in developing diabetes.67)
We also found that catechin-rich green tea prevented liver fibrosis after hepatic injury induced by galactosamine through the down-regulation of the gene expression of collagens.68) Thus, green tea appears to have hepatoprotective effects. From a clinical point of view, the application of catechins to therapy for hepatitis C appears to be promising.69) However, it should be noted that hepatotoxicity associated with supplements containing green tea has been reported,70) although animal experiments showed no evidence of characteristic hepatotoxicity in rats treated with very large amounts of different green tea extracts.71)
Research into the relationship between green tea and obesity-related insulin resistance syndrome has shown that green tea enhances insulin activity in vitro,72) enhances insulin sensitivity in human subjects73) and rats,74) and reduces hypertriacylglycerolaemia in mice.75) One of the hallmarks of diabetes is the inability of insulin to inhibit hepatic glucose production.76) Increased gluconeogenesis is a main source of increased hepatic glucose production and the ability of insulin to regulate transcription of the rate-controlling gluconeogenic enzymes, phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase), may contribute to this problem.
In experiments using rat hepatoma H4IIE cells, EGCG was shown to mimic the cellular effects of insulin including the reductive effect on the gene expression of these gluconeogenic enzymes.76) It is very important to know whether or not such finding in vitro is relevant to the in vivo situation. We demonstrated that administration of EGCG caused a reduction in the level of mRNAs for these gluconeogenic enzymes in the mouse liver.77) Green tea was also shown to down-regulate the gene expression of these gluconeogenic enzymes.77) Wolfram et al.78) reported a pronounced decrease of glucose levels in food-deprived db/db mice treated with EGCG. The results for gene expression in liver and adipose tissues of db/db mice supplemented with EGCG for 7 weeks showed that PEPCK expression was significantly down-regulated in the adipose tissue, although the down-regulation was not significant statistically in the liver.
Our recent findings indicate that EGCG down-regulates the gene expression of these gluconeogenic enzymes by reducing the gene and protein expression of hepatocyte nuclear factor (HNF)4α, a key transcription factor for PEPCK and G6Pase79) (Fig. (Fig.5).5). Insulin is known to reduce the protein expression of HNF4α80) and, therefore, EGCG has an insulin-mimetic property in this sense. EGCG also reduced the intestinal expression of these gluconeogenic enzymes in association with the down-regulation of HNF4α and HNF1α.81)
In a more recent study, we showed that an EGCG-free fraction derived from a green tea infusion had effects similar to those of EGCG.82) The hot water infusion of green tea leaves was separated into an ethanol-soluble fraction and an EGCG-free water-soluble fraction (GT-W). GT-W reduced the gene expression of G6Pase and PEPCK in H4IIE cells and caused a decrease in expression of the transcription factor HNF4α. Reduced levels of PEPCK and HNF4α proteins were demonstrated in the cells treated with GT-W. Administration of GT-W to mice for 4 weeks reduced the hepatic expression of G6Pase, PEPCK, and HNF4α. However, the action mechanism appears different because EGCG’s action was attenuated by a reducing agent, N-acetylcysteine,82) suggesting a change in the redox state of the cells to be involved, whereas the activity of GT-W was not affected by this agent.83) These results suggest that green tea consumption and dietary supplementation with EGCG could potentially contribute to nutritional strategies for the prevention and treatment of type 2 diabetes mellitus through their effects to reduce the fasting blood glucose concentration by down-regulating the hepatic gene expression of gluconeogenic enzymes.76,78)
A recent large-scale retrospective cohort study revealed that consumption of green tea, coffee, and total caffeine was associated with a reduced risk for type 2 diabetes mellitus.84) Panagiotakos et al.85) reported that long-term tea intake was associated with reduced levels of fasting blood glucose and a lower prevalence of diabetes, in a cohort of elderly people living on Mediterranean islands.