Cyclin D1/CDK4 Complex in Hepatocyte Proliferation

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DESCRIPTION (provided by applicant): It is now recognized that alterations in metabolism play a critical role in proliferating and malignant cells. In order to provide for the energy and anabolic requirements of growth and proliferation, cells must undergo substantial metabolic adaptations through mechanisms that are incompletely characterized. In this application for a renewal of my R01 grant, we propose to examine how cyclin D1 regulates key aspects of metabolism in the liver and hepatocellular carcinoma (HCC). Cyclin D1 is a cell cycle control protein that promotes progression through critical checkpoints in G1 phase and is also one of the most prevalent oncogenes in human cancers (including HCC). It is expressed at low levels in normal liver, but is markedly induced during hepatocyte proliferation and in cancer. Our prior studies have shown that cyclin D1 plays an important role in the hepatocyte cell cycle, and in fact is sufficient to promote proliferation of these cells and liver growth in the absence of other stimuli. Our more recent data have found that cyclin D1 regulates metabolism through direct repression of two key transcription factors, HNF4α and PPARα, which play an important role in the liver. The modulation of these transcription factors by cyclin D1 has several potentially important implications, including a shift in metabolism away from activities that support systemic homeostasis and decreased fatty acid oxidation, leading to fatty liver. Our data also indicate that cyclin D1 promotes glycolysis, a key anabolic feature of growth. In Aim 1A of this proposal, we will examine the regulation of HNF4α by cyclin D1, which has implications for broad aspects of homeostatic metabolism in the regenerating liver and HCC. In Aim 1B, we will examine the mechanisms by which cyclin D1 regulates PPARα activity, which plays an important role in lipid utilization. In Aim 2, we will use biochemical and advanced metabolomic techniques to study the mechanisms by which cyclin D1 regulates lipid homeostasis, and to define how this protein modulates the flux of glucose and glutamine into key metabolic pathways. We believe that these studies will significantly advance the understanding of how cyclin D1 promotes growth, proliferation, and cancer through metabolic regulation.