Epigallocatechin-3-gallate improves nonalcoholic steatohepatitis model mice expressing nuclear sterol regulatory element binding protein-1c in adipose tissue

Abstract

Abstract. We examined whether or not epigallocatechin-3-gallate (EGCG) improves liver injury of nonalcoholic steatohepatitis (NASH) model mice expressing nuclear sterol regulatory element-binding protein 1c in adipose tissue. nSREBP-1c transgenic C57BL6 mice aged 30 weeks were divided into group 1 (no treatment), group 2 (ascorbic acid alone), group 3 (ascorbic acid and 0.05% EGCG), and group 4 (ascorbic acid and 0.1% EGCG). At 42 weeks, we performed measurement of liver weight to body weight, biochemical assays, morphometry of liver specimens, immunohistochemistry for 8-hydro-2'-deoxyguanosine (8-OhdG), and Western blotting for insulin and TNF-· signalings. Ratio of liver weight to body weight in the high dose EGCG-treated group (group 4) was significantly lower than those of groups 1 and 2 (p<0.05 and <0.01, respectively). Blood ALT, glucose, total cholesterol, and triglyceride levels of group 4 were significantly low compared with those of the EGCGnon-treated group (groups 1 and 2) (p<0.05, respectively). The degrees of steatosis, inflammation, ballooning hepatocytes and Mallory-Denk bodies in group 4 significantly improved compared with those in other groups (p<0.05, respectively). The 8-OhdG immunolocalization in liver tissues of the group 4 obviously decreased compared with those of groups 2 and 3. For Western blotting, the expressions of insulin receptor substrate-1 (IRS-1) and phosphorylated IRS-1 (pIRS-1) in liver tissues of group 4 increased compared with those of groups 2 and 3. On the other hand, the expressions of pAkt, pIKKß and pNF-κB decreased compared with those of groups 2 and 3. From these results, EGCG reduces inflammation, insulin resistance and oxidative stress, and suppresses liver injury in nSREBP-1c transgenic mice. IntroductionAlthough the obesity epidemic is a worldwide phenomenon, the severity of the epidemic differs greatly from region to region. The prevalence of obesity among Japanese adults is 3.4% in males and 3.8% in females, and is around one tenth of that in the USA (1). In addition, currently in Japan almost 30% of adult males and females over 50 years old are obese. This rising incidence of obesity parallels the dramatic increase in fatty liver in these age groups. Based on annual health checks, the prevalence of fatty liver diagnosed by ultrasonography increased from 10% in 1980 to 20-40% in 2000 among adults. Thus, nonalcoholic fatty liver disease (NAFLD) is now emerging as the most common liver disease in Japan (2,3). The recent worldwide rise in the number of patients with nonalcoholic steatohepatitis (NASH) tends to parallel the increase in metabolic syndrome, which includes obesity, type 2 diabetes and hyperlipidemia (4).NAFLD mainly comprises of simple steatosis that is considered benign, however some patients have nonalcoholic steatohepatitis (NASH), which is a clinicopathological entity characterized by the development of hepatic histological changes resembling those induced by excessive alcohol intake that occur in the absence of alcohol abuse (5). Some patients w...

Therapeutic potential of green tea in nonalcoholic fatty liver disease

“…57 EGCG protects against NASH in the adipose SREBP-1c overexpression model by decreasing the expression of hepatic phosphorylated Akt, phosphorylated inhibitor of nuclear factor kappa-B (NFkB), and phosphorylated NfkB. 104 Consistent with these findings, recently completed studies found that ob/ob mice developed severe liver steatosis with moderate inflammation that was attenuated by GTE. 158 Greater inflammatory cell activation in obese mice was evidenced by greater hepatic expression of inducible nitric oxide synthase, NADPH oxidase, and myeloperoxidase, whereas GTE normalized the expression and activity of these inflammatory enzymes to the level of lean controls.…”

“…102 The same dose of EGCG provided to mice overexpressing SREBP-1c for 12 weeks reduced histological evidence of hepatocyte ballooning and Mallory-Denk bodies. 104 EGCG protected against inflammation in these models but did not protect against fibrosis. By contrast, 3% microbially fermented GTE containing primarily ECG and gallocatechin had no effect on inflammation in rats fed a high-fat, choline-deficient diet and given daily intraperitoneal injections of nitrite, but it normalized fibrosis as evidenced by histological findings.…”

“…103 EGCG provided in the drinking water (1 g/L) decreased histological steatosis grading in rats fed a high-fat diet for 6 weeks 102 and in mice overexpressing SREBP-1c and fed a standard rodent diet for 12 weeks. 104 A microbially fermented GTE (3%, wt/wt) containing primarily ECG and gallocatechin, but low amounts of EGCG, was also effective in reducing hepatic triglyceride levels in rats fed a choline-deficient, high-fat diet for 10 weeks. 82 GTE has several protective bioactivities that would be expected to prevent liver steatosis, which include decreasing lipid and carbohydrate absorption, decreasing DNL and adipose lipolysis, increasing b-oxidation and thermogenesis, and improving insulin sensitivity.…”

“…Others have shown protection against NASH mediated by GTE or its catechins to be associated with decreased hepatic lipid peroxidation and increased plasma superoxide dismutase activity in the high-fat, choline-deficient model, 82 decreased hepatic lipid peroxidation and increased hepatic glutathione in the high-fat diet model, 102 and decreased oxidative DNA damage in the SREBP-1c overexpression model. 104 GTE may decrease oxidative stress either directly, by scavenging reactive oxygen and nitrogen species, or indirectly, by activating the Nrf2 pathway.…”

Green tea polyphenol epigallocatechin-3-gallate ameliorates insulin resistance in non-alcoholic fatty liver disease mice

“…Recent studies have shown a strong correlation between the consumption of green tea and the prevention of NAFLD. Other studies have shown that EGCG reduced the severity of liver injury by reducing circulating insulin, improving insulin sensitivity and attenuating insulin resistance in type 2 diabetes mellitus (T2DM) or NAFLD mice [12][13][14] . Although EGCG reduces circulating insulin, it is not clear whether IDE is involved.…”