The liver manages a wide range of metabolic functions, which are controlled by interrelated signaling pathways. One such pathway involves cytosolic Ca2+ signaling in hepatocytes, which regulates activities such as transport and bile secretion, cytoskeletal organization, and apoptosis. The ongoing goal of this Program Project is to examine the mechanisms and effects of a complementary Ca2+ signaling system, within the nucleus of hepatocytes. During the current award it was found that growth factors act through a previously unrecognized Ca2+ signaling pathway in the nucleus of hepatocytes to regulate cell proliferation, that protein modification by 0-GlcNAcylation is a potential new control mechanism for the molecular regulation of the lnsP3 receptor/Ca2+ release channel, and that the nuclear-specific MAPK phosphatase MKP-1 is involved in the regulation of lipid metabolism and development of hepatic steatosis. During the next award period we will test the hypothesis that the balance between growth and metabolism in the liver is regulated by Ca2+ signals in the nucleus of hepatocytes. This will be tested through three projects. Project 1 will determine how receptor tyrosine kinases control Ca2+ signaling in the nucleus to regulate hepatocyte growth, and how fatty liver impairs these pathways. Project 2 will investigate the effects of fatty acids and glucose on 0-GlcNAcylation of the lnsP3 receptor in the nucleus and cytosol, and how this affects Ca2+ signaling in hepatocytes. Project 3 will test whether stress in the ER and nucleus impairs nuclear Ca2+ signaling and promotes hepatic steatosis by disrupting MKP-1-mediated regulation of MAPK targets that control hepatic lipogenesis. To help carry out these projects, core facilities will be established for cell and molecular biology, cell imaging, and administration. These projects will collectively provide a comprehensive investigation of how nuclear Ca2+ regulates the balance between growth and metabolism in the liver. The results of these studies will have broad clinical implications for the treatment of liver diseases in which regulation of hepatic growth is impaired, including cirrhosis and hepatocellular carcinoma, as well as metabolic syndromes such as non-alcoholic fatty liver disease (NAFLD).

Public Health Relevance

Non-alcoholic fatty liver disease (NAFLD) is an increasingly common clinical problem. It can cause liver cirrhosis by itself, and it can accelerate the progression of other liver diseases as well. This group of projects will collectively test whether and how NAFLD adversely affects the liver by interfering with cell signaling pathways within the nucleus of hepatocytes.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Program Projects (P01)
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Special Emphasis Panel (ZDK1-GRB-8 (J1))
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Serrano, Jose
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Yale University
Internal Medicine/Medicine
Schools of Medicine
New Haven
United States
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