The liver is a major metabolic organ responsible for maintaining whole-body homeostasis in a changing environment. Given the worldwide use of alcohol, the epidemic of obesity and viral infection, liver damage is common in clinical practice. The molecular mechanisms that control the balance between hepatocyte life and death in response to chronic liver injury remain largely elusive. O-linked ?-N-acetylglucosamine (O-GlcNAc) modification has emerged as an important regulatory mechanism underlying normal liver physiology and metabolic disease. This prevalent and dynamic post-translational modification is controlled by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). We recently found that liver-specific OGT knockout mice develop hepatomegaly, ballooning degeneration, and fibrosis in the liver. We therefore hypothesize that OGT acts as a critical molecular switch between hepatocyte survival and death in response to chronic liver injury. To test this hypothesis, we propose to undertake three specific aims.
Aim 1 will define the role of OGT in pathogenesis of liver injury;
Aim 2 will identify the critical targets of OGT in hepatocyte survival and death;
Aim 3 will determine the functional importance of OGT regulation of necroptosis in liver injury. Successful completion of this project will provide critical insights into the role of OGT in regulating the balance between hepatocyte survival and death and the onset of liver injury. Detailed investigation of liver-specific OGT knockout mice will likely establish a useful mouse model that recapitulates features of human liver injury, and facilitate therapeutic target identification for prevention and treatment of chronic liver disease.
Chronic liver disease affects over one third of Americans and over one billion people worldwide. This project will investigate how the O-GlcNAc signaling pathway regulates the balance between hepatocyte life and death in response to chronic liver injury. The results of these studies will have broad clinical implications for understanding the etiology of liver diseases resulting from exposure to alcohol, hepatitis viruses, and other hepatotoxins.
|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|
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