Molecular Mechanisms of Lycopene Actions on Liver Disease Outcomes.
IP, Blanche Chee Hinn Yih.
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... read moreand various 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
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.
Keywords: Nutrition, and Biochemistry.read less