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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
5P01DK057751-13
Application #
8463504
Study Section
Special Emphasis Panel (ZDK1-GRB-8 (J1))
Program Officer
Serrano, Jose
Project Start
2000-04-01
Project End
2016-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
13
Fiscal Year
2013
Total Cost
$1,424,224
Indirect Cost
$560,782
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Qian, Kevin; Wang, Simeng; Fu, Minnie et al. (2018) Transcriptional regulation of O-GlcNAc homeostasis is disrupted in pancreatic cancer. J Biol Chem 293:13989-14000
Boeckel, Göran R; Ehrlich, Barbara E (2018) NCS-1 is a regulator of calcium signaling in health and disease. Biochim Biophys Acta Mol Cell Res :
Lawan, Ahmed; Min, Kisuk; Zhang, Lei et al. (2018) Skeletal Muscle-Specific Deletion of MKP-1 Reveals a p38 MAPK/JNK/Akt Signaling Node That Regulates Obesity-Induced Insulin Resistance. Diabetes 67:624-635
Franca, Andressa; Filho, Antonio Carlos Melo Lima; Guerra, Mateus T et al. (2018) Effects of endotoxin on type 3 inositol 1,4,5-trisphosphate receptor in human cholangiocytes. Hepatology :
Lemos, Fernanda O; Ehrlich, Barbara E (2018) Polycystin and calcium signaling in cell death and survival. Cell Calcium 69:37-45
Yang, Xiaoyong; Qian, Kevin (2017) Protein O-GlcNAcylation: emerging mechanisms and functions. Nat Rev Mol Cell Biol 18:452-465
Giehl, Esther; Lemos, Fernanda O; Huang, Yan et al. (2017) Polycystin 2-dependent cardio-protective mechanisms revealed by cardiac stress. Pflugers Arch 469:1507-1517
Feriod, Colleen N; Oliveira, Andre Gustavo; Guerra, Mateus T et al. (2017) Hepatic Inositol 1,4,5 Trisphosphate Receptor Type 1 Mediates Fatty Liver. Hepatol Commun 1:23-35
Kruglov, Emma; Ananthanarayanan, Meenakshisundaram; Sousa, Pedro et al. (2017) Type 2 inositol trisphosphate receptor gene expression in hepatocytes is regulated by cyclic AMP. Biochem Biophys Res Commun 486:659-664
Lawan, Ahmed; Bennett, Anton M (2017) Mitogen-Activated Protein Kinase Regulation in Hepatic Metabolism. Trends Endocrinol Metab 28:868-878

Showing the most recent 10 out of 113 publications