Investigation of the molecular mechanisms by which alcohol initiates hepatic injury and promotes carcinogenesis and the prevention of these pathologies through dietary tomato intervention.
and excessive consumption of alcohol leads to the development of alcoholic liver disease
(ALD) and is a major risk factor for hepatocellular carcinoma (HCC). Induction of the
cytochrome p450 2E1 (CYP2E1) enzyme and inflammatory responses by alcohol play a role in
the pathogenesis of both ALD and HCC. Avoidance of chronic or excessive alcohol intake
is the best protection aga... read moreinst alcohol-related liver injury; however, the social
presence and addictive power of alcohol are strong. Therefore, mechanistic studies are
essential and dietary intervention represents a promising disease control strategy for
the prevention of ALD and HCC. The primary objective of this thesis is to investigate
the molecular mechanisms by which excessive alcohol initiates ALD and promotes HCC and
prevention of these injuries through dietary means. First, we utilized a tumor
progression locus 2 (TPL2) knockout model to demonstrate that TPL2, a kinase that
functions as a key regulator in inflammatory pathways, plays a novel role in the
pathogenesis of ALD. This provides crucial insight into the molecular mechanisms behind
ALD development. Second, we established an effective diethylnitrosamine (DEN)-initiated
alcohol-promoted pre-neoplastic liver lesion mouse model. This model utilizes C57BL/6
mice that were DEN-initiated at 14 days of age. At 8 weeks of age, 27% Lieber-DeCarli
alcoholic diet was fed for a promotional period of 21 days. This model provides an ideal
environment in which to further elucidate the mechanisms by which alcohol promotes HCC
development and identify potential therapeutic targets for treatment. Third, we
demonstrate that purified lycopene, a carotenoid found in tomatoes, and the lycopene
metabolite apo-10'-lycopenoic acid promote alcohol-induced inflammation while tomato
extract (lipid soluble tomato components) has no effect on liver injury and tomato
powder (representative of whole tomato) possesses a unique biological function that
inhibits ALD and alcohol-promoted pre-neoplastic liver lesions through the potential
mechanism of CYP2E1 protein down-regulation. Our findings support whole food as an
effective disease prevention strategy and highlight the dangerous interactions between
alcohol consumption and supplementation with purified
Thesis (Ph.D.)--Tufts University, 2013.
Submitted to the Dept. of Biochemical and Molecular Nutrition.
Advisor: Xiang-Dong Wang.
Committee: Lynne Ausman, and Andrew Greenberg.
Keywords: Nutrition, Biochemistry, and Molecular biology.read less