The liver has a unique ability to grow and regenerate. Liver regeneration is mediated largely by Hepatocyte Growth Factor (HGF) and other growth factors, which act through specific receptor tyrosine kinases (RTKs). However, liver regeneration is impaired in fatty liver disease. During the previous grant cycle we found that cell proliferation in the liver depends on increases in Ca2-i- in the nucleus rather than in cytosol, that changes in nuclear Ca2+ in hepatocytes are mediated by inositol 1,4,5-trisphosphate (lnsP3), and that the RTKs that mediate growth translocate from the cell membrane to the nucleus to locally form lnsP3 and increase Ca2+. While it is established that fatty liver induces endoplasmic reticulum (ER) stress, our preliminary data suggest that fatty liver also induces markers of ER stress within the nuclear envelope and the nucleoplasmic reticulum (NR). A causal link between fatty liver, ER/NR stress, and altered Ca2+ signaling in the nucleus may provide a novel mechanism by which fatty liver disease impairs liver regeneration. Because as many as a third of adults in the US may have NAFLD, this balance between hepatic growth and metabolism is an important clinical problem. We hypothesize that RTKs regulate growth in the liver by inducing lnsP3-mediated Ca2+ signals within the nucleus, but this pathway is impaired by the metabolic changes associated with NAFLD. We will use the HGF receptor c-Met as a model RTK to test this through the following specific aims: (1) The mechanism by which c-Met moves from the plasma membrane to the interior of the nucleus will be determined;(2) The mechanism by which intranuclear c-Met locally generates lnsP3 and thus nuclear Ca2+ signals will be identified;and (3) The effects of NAFLD and induction of ER/NR stress on nuclear Ca2+ signaling pathways and liver growth and regeneration will be examined. These studies will reveal how growth factors and their corresponding RTKs control nuclear Ca2+, and identify whether and how this is impaired in fatty liver, which in turn may give new insights as to why liver regeneration is impaired in NAFLD. Together with Projects 2 and 3, this project should provide an integrated understanding of how nuclear Ca2+ signaling pathways regulate the balance between growth and metabolism in the liver.
Up to one third of American adults have fatty liver disease. This leads to health problems that include impaired growth and repair of the liver in response to other injuries. This project will test whether and how the presence of fat in liver cells inhibits the transmission of signals to the cell nucleus that are necessary to maintain normal liver growth.
|Yang, Xiaoyong; Qian, Kevin (2017) Protein O-GlcNAcylation: emerging mechanisms and functions. Nat Rev Mol Cell Biol 18:452-465|
|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|
|Wang, Simeng; Yang, Xiaoyong (2017) Inter-organ regulation of adipose tissue browning. Cell Mol Life Sci 74:1765-1776|
|Lee, Hojin; Min, Kisuk; Yi, Jae-Sung et al. (2017) A Phosphoproteomic Screen Identifies a Guanine Nucleotide Exchange Factor for Rab3A Protein as a Mitogen-activated Protein (MAP) Kinase Phosphatase-5-regulated MAP Kinase Target in Interleukin 6 (IL-6) Secretion and Myogenesis. J Biol Chem 292:3581-3590|
|Giehl, Esther; Lemos, Fernanda O; Huang, Yan et al. (2017) Polycystin 2-dependent cardio-protective mechanisms revealed by cardiac stress. Pflugers Arch :|
|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 :|
|Lawan, Ahmed; Bennett, Anton M (2017) Mitogen-Activated Protein Kinase Regulation in Hepatic Metabolism. Trends Endocrinol Metab 28:868-878|
|Zhao, Lin; Feng, Zhihui; Yang, Xiaoyong et al. (2016) The regulatory roles of O-GlcNAcylation in mitochondrial homeostasis and metabolic syndrome. Free Radic Res 50:1080-1088|
|Wang, Baisheng; Boeckel, Göran R; Huynh, Larry et al. (2016) Neuronal Calcium Sensor 1 Has Two Variants with Distinct Calcium Binding Characteristics. PLoS One 11:e0161414|
Showing the most recent 10 out of 105 publications