1a. Objectives (from AD-416)
1. Determine whether high fat diet induced non-alcoholic steatohepatitis is a promoting factor in hepatic carcinogenesis. 2. Determine whether dietary lycopene will protect against high fat diet promoted liver cancer development.
1b. Approach (from AD-416)
We will use both high fat diet-induced nonalcoholic steatohepatitis (NASH) rats and genetically-induced obese mice with injections of liver-specific carcinogen,diethylnitrosamine, followed by treatment with tomato extract or lycopene for both short and long durations. We will focus on the role of the stress-activated protein c-Jun-NH2-kinase (JNK) signaling, a key component mediating the high fat-induced oxidative stress and inflammatory processes, in response to tomato extract and lycopene supplementation on both cell proliferation/apoptosis, inflammation and premalignant and malignant lesions in obesity related hepatic tumorigenesis. Wewill complement animal study with cell culture studies (e.g., use siRNA silencing of JNK) using human hepatocyte lines and liver cancer cells to facilitate mechanistic studies to determine the contribution of the JNK signaling pathway to lycopene action. Since adiposity contributes to the increased incidence and/or death from liver cancer, we will examine metabolic alteration, including insulin resistance,and pro-inflammatory signaling in intra-abdominal fat tissue and its potential contribution to hepatic carcinogenesis. Once we establish that there is an association between metabolic alteration and hepatic carcinogenesis, we will examine insulin and insulin growth factors (IGF-I/IGF-II) signaling cascades and address their differential activation in NASH and its related hepatic carcinogenesis, as well as potential actions of tomato extract and lycopene prevention against the onset of high fat diet/obesity-related liver disease.
3. Progress Report
Obesity-related hepatic steatosis (fatty liver) is very common, occurring in at least 20% of American adults. In addition, data from NHANES III and clinical liver biopsy studies estimate that non-alcoholic steatohepatitis (called “NASH” or fatty liver with inflammation), prevalence is around 7% in the North American population. Although the best protection against NASH/obesity-related diseases, including diabetes, cardiovascular disease and certain cancers, is the avoidance of excessive fat intake and maintenance of a healthy body weight, the overweight/obesity epidemic is spreading and the severe health risks will persist for many years. Utilization of nutritional interventions to protect tissue against high fat-generated cell damage and inflammation may be an appropriate and effective strategy to modify NASH and its associated cancer risk, specifically, liver cancer. For the past year, we have demonstrated that liver cell death (apoptosis) was significantly increased in NASH induced by high fat diet. The increased liver damage and its associated molecular stress activation as well as an imbalance of pro- and anti-apoptotic proteins all contributed to high liver cell death plays a significant role in causing NASH. We also demonstrated that alcohol consumption even at a moderate level in a pre-existing NASH condition led to more liver inflammation and cell death. Our results indicate that persons with NASH should take great caution when consuming alcohol. These studies provide useful information regarding potential molecular targets for NASH prevention and treatment; and tomato extract, not lycopene alone, may have an anti-inflammatory effect against NASH, which is associated with obesity/high fat diet. Since tomato is an excellent source of both lycopene and other functional constituents including beta -carotene, vitamin E, vitamin C, etc.,our results indicate that tomato extract could be effective against inflammatory damage due to the combined or synergistic effects of lycopene with other constituents found in tomatoes. For publications related to this project, see parent project #1950-51000-074-00D.
1. A High-fat Diet May Promote Liver Cancer One of the consequences of the current obesity epidemic is increased rates of nonalcoholic fatty liver disease, a chronic liver disease in adults and children. This ultimately leads to cirrhosis and end-stage liver disease, such as liver cancer. The increasing incidence of liver cancer in the United States has paralleled the epidemic of obesity. Several large population studies have revealed that obese people have a higher risk of incidence or mortality of liver cancer, however, there is still a need for data on the relationship between inflamed liver, and liver cancer. ARS-funded researchers from Tufts University in Boston, MA were the first to use an animal model to demonstrate that a high-fat diet induced nonalcoholic steatohepatitis (NASH) promotes liver cancer development. This animal study will provide the foundation to develop effective dietary components for the prevention of obesity/NASH related liver disease including cancer.
2. Lycopene, a Nutrient in Tomatoes, May Inhibit Some Forms of Liver Cancer The beneficial effects of carotenoid-rich fruits and vegetables on cancer risk have been found in many studies, with strong evidence that tomatoes and tomato products as well as tomato carotenoids (lycopene, phytoene, and alpha-tomatine) have important health benefits. Although there is strong supporting evidence from both animal and cell culture studies that these carotenoids inhibit liver tumor growth, our understanding of how carotenoids function against tumorigenesis, particularly against obesity-related hepatic tumorigenesis, is far from complete. ARS-funded researchers from Tufts University in Boston, MA were the first to show in an animal model that lycopene and tomato extract inhibit nonalcoholic steatohepatitis (NASH)-promoted liver cancer. These findings are crucial in order to determine the prevention efficacy of carotenoids in inhibting obesity/high fat diet promoted liver cancer development.