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.
Nonalcoholic fatty liver disease (NAFLD) is a the most common liver disease in the world, yet insufficient understanding of the mechanistic processes driving its initiation and progression have prevented development of effective diagnostic and therapeutic tools. The goal of the proposed research is to gain insight into these processes so that they can be exploited to benefit NAFLD patients.
| Tschida, Barbara R; Temiz, Nuri A; Kuka, Timothy P et al. (2017) Sleeping Beauty Insertional Mutagenesis in Mice Identifies Drivers of Steatosis-Associated Hepatic Tumors. Cancer Res 77:6576-6588 |
