Hepatoprotection of Vitamin E and Green Tea on Oxidative Stress and Inflammatory Responses In Animal Models of Obesity-Triggered Nonalcoholic Fatty Liver Disease.

摘要

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide and is a leading cause of abnormal liver enzymes in the United States. The prevalence of NAFLD has risen in parallel with the increasing rate of obesity, which is now at epidemic proportions. Obesity and insulin resistance are the "first-hits", leading to hepatic steatosis. Steatotic livers are vulnerable to oxidative stress and inflammation-mediated "second-hits", which play pivotal roles in the etiology of NAFLD. To date, there are no validated treatments for NAFLD beyond weight management. The involvement of oxidative stress and inflammation suggests that dietary antioxidants and functional foods may mitigate the pathogenic events implicated in its progression. Thus, the central hypothesis of this dissertation is that vitamin E (as RRR-alpha- or -gamma-tocopherol) or green tea extract (GTE; containing 30% catechins) would mitigate obesity-induced oxidative stress and inflammatory responses in genetic or diet-induced obese experimental models of NAFLD. alpha- and gamma-Tocopherol supplementation attenuated lipopolysaccharide (LPS)-induced hepatic injury by mitigating hepatic lipid peroxidation and inflammatory responses without affecting hepatic steatosis. This indicates that alpha- and gamma-tocopherols protect against the development of NASH without affecting the "first-hits" of NASH. To further examine whether green tea catechins, which are known to have hypolipidemic, antioxidant, and anti-inflammatory activities, regulate the "multiple-hits" implicated in the development of NASH, studies were conducted to evaluate the hepatoprotective activity of GTE on obesity-induced NASH. GTE reduced body weight and adiposity without affecting food intake in genetically obese (ob/ob) mouse model of NASH. GTE also attenuated obesity-triggered liver injury by reducing lipid peroxidation and nitrative damage, which was accompanied by decreased activity and expression of inflammatory proteins. Since ob/ob mice do not fully recapitulate the pathogenic events leading to NASH in humans, the hepatoprotective activity of GTE on NASH was also evaluated in an obese model of high-fat feeding. GTE mitigated hepatic prostaglandin E2 (PGE2) accumulation and lipid peroxidation by suppressing cyclooxygenase-2 (COX-2) activity and reducing its protein expression levels. Although GTE reduced total arachidonic acid accumulation in the liver, the flux of arachidonic acid from the phospholipid to the non-esterified fatty acid (NEFA) pool was unaffected by GTE. Thus, GTE attenuates the development of obesity induced NASH by reducing liver steatosis and injury, and decreasing the levels of pro-inflammatory mediators known to be produced from activated inflammatory cells. Collectively, this dissertation provides novel evidence that vitamin E and green tea are useful dietary strategies that may attenuate the growing prevalence of NAFLD observed in humans.