Abstract: The prevalence of non-alcoholic fatty liver disease (NAFLD) is positively associated with the obesity epidemic, and with the risks for cardiovascular disease (CVD) and liver cancer. Dysregulated hepatic lipid metabolism and liver inflammation play critical roles in the pathogenesis of NAFLD-associated diseases. The intake of lycopene-rich foods is inversely linked with risks for CVD and ... read morevarious cancers. Therefore, increasing dietary intake of lycopene may represent an important disease prevention strategy. The enzyme beta-carotene 9',10'-oxygenase (BCO2) metabolizes lycopene by cleavage at the 9',10' double bond, and generates metabolites including apo-10'-lycopenoic acid (APO10LA). The primary objective of this thesis was to investigate whether BCO2 expression is crucial for biological functions of lycopene and APO10LA, and to elucidate the molecular mechanisms by which lycopene and APO10LA each mediate their protective effects against high saturated fat diet (HFD)-associated liver injury. Our first study demonstrated that APO10LA supplementation at 10 mg/kg diet inhibited carcinogen-initiated, HFD-promoted hepatic inflammation and tumorigenesis in C57Bl/6J wild-type mice. The chemopreventive effects of APO10LA were associated with increased hepatic sirtuin 1 (SIRT1) protein and deacetylation of SIRT1 targets. In addition, APO10LA suppressed proliferative markers but induced pro-apoptotic markers in transformed cells within liver tumors. In a second study, we use the BCO2-knockout (BCO2-KO) mouse model to compare the potential effects of lycopene and APO10LA supplementation to inhibit HFD-associated hepatic steatosis. Similar to the first study, APO10LA-mediated steatosis and inflammation suppression was associated with up-regulated hepatic SIRT1 signaling activation, and with reduced liver cholesterol content. Interestingly, lycopene-mediated steatosis suppression in BCO2-KO mice was not associated with the mechanisms modulated by APO10LA. Dietary lycopene modulated genes involved increasing fatty acids (FA) &beta-oxidation, FA uptake, and mitochondrial uncoupling in mesenteric adipose tissue (MAT), suggesting that lycopene-mediated steatosis reduction may be associated with increased FA utilization in MAT. Our final study demonstrated that both lycopene and APO10LA supplementation were effective in inhibiting carcinogen-initiated, HFD-promoted liver tumorigenesis in BCO2-KO mice as well as the respective wild-type. However, different mechanisms were modulated by lycopene in wild-type and BCO2-KO mice, suggesting that lycopene metabolism by BCO2 can modify lycopene activity on the biochemical level. In summary, these studies demonstrated that lycopene and APO10LA supplementation are both protective against HFD-associated liver injuries in mouse strains with different abilities to metabolize lycopene. Our observations revealed the unique biological activities exerted by lycopene and APO10LA that served to inhibit a broad-range of HFD-associated liver diseases. These findings supports the conclusion that both lycopene and APO10LA are effective liver disease prevention strategies and provide the foundation for future animal and human studies to examine the efficacy and mechanisms by which lycopene or APO10LA supplementation prevents HFD-related hepatic injury.
Thesis (Ph.D.)--Tufts University, 2014.
Submitted to the Dept. of Biochemical and Molecular Nutrition.
Advisor: Xiang-dong Wang.
Committee: Lynne Ausman, Alice Lichtenstein, and Martin Obin.