Metabolic Regulation of Liver Growth

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Liver disease is a common cause of rising morbidity and mortality in the United States: approximately 400,000 patients suffer from chronic liver disease. Cirrhosis, a complication of chronic liver disease is an established risk factor for the development of hepatocellular carcinoma (HCC), which affects over 750,000 patients annual- ly world-wide. Despite this known causality, there are no effective therapies to prevent liver cancer growth in cirrhotic patients. The ability of cancers to proliferate rapidly is well described. It is, however, still largely unknown what enables cancers to grow and how they generate the fuel and necessary cellular building blocks to divide. Hippo signaling, through its transcriptional effector Yap, is a major regulator of organ size and growth in several tissues, including the liver. Alterations in Hippo/Yap activity may be early events in hepato- cellular carcinoma formation. It is unclear, however, how Hippo/Yap provides for the metabolic demands of rapid cell growth. Using the zebrafish (Danio rerio), we have successfully elucidated regulatory roles for nuclear and G protein-coupled receptors in liver development and regeneration, and identified compounds to treat toxic liver injury. Further, we discovered an important role for glucose metabolism in blood vessel and stem cell formation. Our Preliminary Work shows that Yap enhances embryonic and adult liver growth, leading to increased cancer susceptibility: Yap1 reprograms hepatic glutamine and glucose metabolism to in- crease nitrogen and carbon utilization for enhanced nucleotide biosynthesis to fuel proliferation. Our long-term goal is to understand the molecular and metabolic mechanisms enabling cell growth during liver development and cancer. Our objective here is to characterize molecular mechanisms by which Hip- po/Yap signaling reprograms glutamine and glucose metabolism to permit liver growth. Our central hy- pothesis is that Yap directly modulates glutamine and glucose metabolism: it enhances transcription of synthe- sis enzymes and transporters to provide nitrogen and carbon for de novo nucleotide and DNA synthesis, fuel- ing cell proliferation. This hypothesis is derived from our preliminary work and increasing recognition of Hippo pathway aberrations in liver cancer. The rationale for our work is that a detailed understanding of the impact of Hippo/Yap and its metabolic consequences for liver growth may reveal potential new targets to prevent liver cancer in patients with cirrhosis. In Specific Aim 1, we seek to define the molecular mechanisms and conse- quences of Yap1-induced enhanced glutamine synthesis, utilizing specifically generated mutants and trans- genic strains and extensive phenotypic, histological and functional characterization. In Specific Aim 2, we will investigate the importance of Hippo/Yap for glucose transport and metabolism to increase nucleotide synthe- sis. We will deploy highly innovative metabolic flux and high-resolution metabolic imaging to define the fate and utilization of nutritional nitrogen and carbon in vivo. Further, we will identify the potential of modulators of glutamine and glucose metabolism to prevent cancer formation or progression in patients with cirrhosis.