PROJECT SUMMARY/ABSTRACT
Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the world, affecting an estimated
one billion individuals. A substantial proportion of NAFLD patients develops progressive disease, which can
eventually lead to liver failure or cancer. NAFLD-associated liver cancer is currently the fastest growing subset
of this deadly malignancy, and its prevalence is expected to continue rising. The molecular mechanisms that
drive disease development and progression are poorly understood at present. As a result, there are currently
no clinical tests to predict NAFLD advancement or treatments to prevent or reverse its course. Our lab has
observed differential susceptibility to high fat, complex carbohydrate (HFCC) diet-induced progressive NAFLD
in distinct inbred mouse strains. While C57BL/6J (B6) males develop liver steatosis, non-alcoholic
steatohepatitis (NASH), fibrosis, cirrhosis, and HCC in response to a high fat diet, A/J males are completely
resistant to these effects. CSS-18A/J mice, which are genetically identical to B6 except for Chromosome 18
(derived from A/J), are susceptible to diet-induced obesity and liver inflammation, but are resistant to advanced
HFCC diet-induced liver pathologies. This unexpected phenotype challenges the prevailing paradigm for
progressive NAFLD pathogenesis, making the model a unique tool with which to study mechanisms of disease
development and progression. Another unique feature of the CSS-18A/J model is its susceptibility to severe
steatosis on a HFSC diet, demonstrating a critical role of carbohydrate complexity on NAFLD development.
Work proposed in Aim 1 will provide detailed characterization of histopathology, gene expression, lipid
metabolism and immunological features, thereby enabling integrative analyses of baseline and dynamic
differences in the response of susceptible and resistant mice to dietary challenge. Aim 2 experiments will
compare diet-induced metabolic phenotypes in mice with four distinct versions of Chr18 on a B6 genomic
background, as well a in a panel of congenic strains derived from CSS-18A/J. Results will establish genetic
causality by narrowing the genomic interval associated with susceptibility to specific diet-induced maladies.
Integration with results from Aim 1 will prioritize candidate genes and variants for functional validation studies.
Overall, the proposed work will identify molecules, genes, and pathways that modulate susceptibility
to NASH, thus providing strong candidates for subsequent translational studies to determine their
potential as clinical targets to reduce the impact of this increasingly common human disease.