5. Prevention of obesity-related fatty liver disease by green tea polyphenols
Hepatic steatosis (fatty liver) is a condition that is defined by fat accumulation within hepatocytes that exceeds 5% of the liver by weight . Initially, it was believed that this condition was mainly attributable to excess alcohol consumption, but studies in the last several decades have also linked obesity and diabetes to the presence of fatty liver . Typically, fatty liver disease related to etiological factors other than alcohol is referred to as non-alcoholic fatty liver disease (NAFLD). In order to distinguish obesity as the driver of steatosis from other causes, we suggest the term obesity-related fatty liver disease (ORFLD). There are several proposed grades of ORFLD that characterize the severity of the condition. Grades 1-2 describe simple steatosis, with mild inflammation, whereas grades 3-4 describe florid steatosis, chronic and acute inflammation throughout the liver, and fibrosis . Currently, NAFLD is the most common form of liver disease [79,80]. It is now widely accepted that NAFLD is the hepatic component of the metabolic syndrome; risk factors for the disease include obesity, insulin resistance, and hypertriglyceridemia [3-5].
Several studies that have reported the effect of tea or tea catechins on hepatic steatosis in animal models. For example, tea catechins have been shown to reduced hepatic steatosis and liver toxicity (as measured by elevated plasma ALT) in rodents treated with ethanol [81-83], tamoxifen , endotoxins , and liver ischemia/reperfusion injury . Fewer studies, however, have examined the effect of tea constituents on high-fat diet-induced liver pathologies. Murase et al. showed that 0.5% green tea extract in the diet for 11 monthssignificantly decreased liver lipid accumulation caused by a high-fat diet in C57BL/6J mice . Another study showed that treatment with 0.2-0.4% tea catechins for 35 weeks significantly decreased inflammation due to fatty liver in LDL-receptor deficient mice on a hypercholesterolemic diet . Bose et al.  have demonstrated that 0.32% dietary EGCG can ameliorate high fat-diet induced ORFLD in C57BL/6J mice. EGCG treatment reduced incidence of hepatic steatosis, liver size (22% decrease), liver triglycerides (69% decrease), and plasma ALT concentration (67% decrease) compared to high fat-fed control mice after 16 weeks.
Accumulation of lipid in the liver can be caused by several pathologies, including an increased availability of free fatty acids for uptake, deregulation of fatty acid oxidation, or increases in de novo lipogenesis . Dysfunction in lipoprotein metabolism may also play a role in the development of hepatic steatosis. Treatments with tea in animal models have shown to modulate several of these conditions (see previous sections). More studies need to be conducted on the specific components of green tea that mediate its benefits on liver function, and the underlying mechanisms of action. For example, EGCG and other catechins decrease fatty acid synthase in cells and cell-free studies [89-91], but effects by specific tea catechins need to be verified in vivo.
6. Concluding Remarks
The complex of conditions which make up MetS are a growing public health issue that carry an enormous potential economic burden. For example, it has been estimated that medical spending related to obesity in the United States in 2006 was approximately $119 billion . Although effective surgical and pharmacological methods have been developed to treat symptoms related to metabolic syndrome, these treatments can be costly and are not without potential adverse effects [93-96] . The development of dietary agents for the prevention or treatment of one or more of the symptoms of MetS, alone or in combination with lifestyle changes and pharmaceutical agents, could represent a cost-effective and safe approach to the problem.
Green tea is already a popular beverage that could be easily deployed as a part of the diet designed to mitigate or prevent the symptoms of MetS. Although a considerable amount of laboratory research has been conducted to demonstrate the efficacy of green tea as a preventive agent for MetS and to understand the underlying mechanisms of action, many questions remain.
As we have discussed in this review, the green tea catechins appear to have activity against MetS, but caffeine may also play a role. At this point, the interactions between the catechins and caffeine with regard to prevention of MetS are poorly understood. Given the stimulatory effects of caffeine, it would be interesting to know how this affects hypertension parameters. Is it possible that caffeine contributes to beneficial effects related to obesity, but worsens hypertension ? How can these differential effects be reconciled to maximize benefit while keeping adverse events to a minimum.
A number of potential mechanisms have been proposed to account for the preventive effects of green tea against symptoms of MetS. These include modulation of lipid absorption and metabolism, enhancement of glucose uptake and utilization, antioxidative activity, and others. Given the extent to which tea catechins bind non-specifically to proteins, it is like that they work through multiple mechanisms of action to exert their preventive effects. Still some of the proposed mechanisms of action are based on in vitro studies, and seem to occur only at high concentrations of the test compounds. In the absence of compelling in vivo data supporting such mechanisms of action, their relevance in vivo remains unclear. Further in vivo studies which examine the temporal and dose-response relationships governing individual mechanisms are needed. Presumably, the key mechanisms of action are those that occur at the lowest effective concentration and can be demonstrated earliest in the intervention.
Finally, the growing number of studies demonstrating the potential beneficial effects of green tea with regard to MetS have lead to the development and marketing of a number of green tea based dietary supplements. Sales of green tea based dietary supplements in 2008 through the food, drug, and mass market channel were $5.5 million (USD) . Although green tea beverage has a long history of safe use in the diet, a more limited number of controlled animal and human studies have been conducted to determine the maximum tolerated dose of green tea components given in alternative formulations such as pills, capsules, etc. No large scale controlled human intervention studies have reported serious adverse effects to date, however a number of observational case reports, as well as laboratory studies have suggested that high doses of green tea polyphenols can cause hepatotoxicity [99,100]. The therapeutic index of these agents must be established, not only when the compounds are delivered via the diet, but also when (as they often are) converted to a bolus formulation (e.g. pill, capsule, tincture). Only with such a complete understanding can the potential benefits of green tea for the prevention of MetS be realized.