Calcium (Ca2+) regulates a wide range of functions in the liver in response to hormonal and nutritional signals. The broad goals of this project are to (1) define how nutrients regulate nuclear and cytosolic Ca2+ signaling through post-translational modifications of the inositol 1,4,5 trisphosphate receptor (lnsP3R), a Ca2+ release channel found in both the endoplasmic reticulum (ER) and nucleoplasmic reticulum (NR) and (2) how the dysregulation of this pathway contributes to metabolic liver disease. Nutrient flux leads to posttranslational modifications of cytoplasmic and nuclear proteins by O-linked P-N-acetylglucosamine (OGlcNAc). This dynamic and reversible modification is emerging as a key nutrient sensor and regulator of cell signaling and metabolic physiology. We recently discovered that the lnsP3R is modified by 0-GlcNAc and that this modification decreases lnsP3R single channel activity and Ca2+ release from ER. Preliminary data generated in this PPG suggest that fatty liver induces stress in the ER as well as the nuclear envelope and NR, which may result in impaired cytosolic and nuclear Ca2+ signaling. Based on these findings, we hypothesize that 0-GlcNAcylation of the lnsP3R is controlled by glucose and free fatty acids, which is translated into regulation of the lnsP3R in distinct subcellular compartments of hepatocytes. These regulatory events are, in turn, involved in the perturbation of Ca2+ signaling by ER/NR stress in nonalcoholic fatty liver disease. We will test this hypothesis through the following specific aims: (1) We will identify the effects of glucose and free fatty acids on 0-GlcNAcylation of the lnsP3R isofomns in the nucleus and cytosol;(2) we will examine whether 0-GlcNAcylation of the lnsP3R alters lnsP3-gated channel activity and subsequent intracellular Ca2+ signaling with nuclear and cytoplasmic specificity;and (3) we will detemnine whether metabolic stress promotes hepatic steatosis by perturbing lnsP3R 0-GlcNAcylation and nuclear Ca2+ signaling. Collectively, these studies will synergize with Projects 1 and 3 to define the role of 0-GlcNAcylation of the lnsP3R in nutrient sensing and the regulation of nuclear Ca2+ signaling in the development of hepatic steatosis.
Non-alcoholic fatty liver disease (NAFLD) is the leading cause of liver disease in Western countries, affecting approximately 20-40% of the population. Defining the role of 0-GlcNAc modification in regulating hepatic Ca2+ signaling will increase our understanding of the molecular underpinnings of liver physiology and disease and help design new strategies for NAFLD therapy and prevention.
| 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 |
| Wang, Simeng; Yang, Xiaoyong (2017) Inter-organ regulation of adipose tissue browning. Cell Mol Life Sci 74:1765-1776 |
| Tzouvelekis, Argyrios; Yu, Guoying; Lino Cardenas, Christian L et al. (2017) SH2 Domain-Containing Phosphatase-2 Is a Novel Antifibrotic Regulator in Pulmonary Fibrosis. Am J Respir Crit Care Med 195:500-514 |
| Iwakiri, Yasuko; Nathanson, Michael H (2017) Alcohol and calcium make a potent cocktail. J Physiol 595:3109-3110 |
| Khamphaya, Tanaporn; Chukijrungroat, Natsasi; Saengsirisuwan, Vitoon et al. (2017) Nonalcoholic fatty liver disease impairs expression of the type II inositol 1,4,5-trisphosphate receptor. Hepatology : |
| Yang, Xiaoyong; Qian, Kevin (2017) Protein O-GlcNAcylation: emerging mechanisms and functions. Nat Rev Mol Cell Biol 18:452-465 |
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