The mitogen-activated protein kinases (MAPKs) regulate liver growth and metabolism. The MAPKs are opposed by the MAPK phosphatases (MKPs) through direct dephosphorylation. The broad goal of this project is to define how MKP-1 is regulated by nuclear Ca2+ in the liver and how these effects influence liver function. In mouse models of obesity MKP-1 is overexpressed and its loss protects against the development of hepatic steatosis. Hence, the regulation of MKP-1 expression is important for the maintenance of hepatic function. Preliminary data generated in this PPG has discovered that hepatic steatosis, which induces endoplasmic reticulum (ER) stress and disrupts cytosolic Ca2-<- homeostasis, also induces markers of ER stress that are localized to the nuclear envelope and the nucleoplasmic reticulum (NR). Moreover, nutrient load perturbs NR-localized inositol-1,4,5-trisphosphate receptor function. These findings suggest that hepatic steatosis induces NR stress and impairs nuclear Ca2+ signaling. Furthermore, we show that nuclear Ca2+ suppresses MKP-1 expression. These observations have led to the hypothesis that NE stress impairs nuclear Ca2-<- signaling and promotes hepatic steatosis by disrupting MKP-1-mediated regulation of MAPK targets that control hepatic lipogenesis. We will test this hypothesis in the following specific aims: (1) We will establish how nuclear Ca2+ negatively regujates the expression of MKP-1. The mechanisms by which nutrients induce MKP-1 expression through Ca2+-dependent and independent pathways will be established;(2) How MKP-1 targets to the nucleus will be defined. The ability of MKP-1 to form complexes with and coordinate the kinetics of activation of hepatic lipogenic genes will be determined;(3) We will test whether nuclear Ca2+ signaling promotes hepatic steatosis by inducing MKP-1 overexpression. The effect that nuclear Ca2+ signaling has on phosphorylation of MKP-1-regulated MAPK targets involved in hepatic lipid metabolism will be established and whether these effects contribute to hepatic steatosis will be ascertained. Collectively, these studies will synergize with Projects 1 and 2 to define the role of nuclear Ca2+ and MKP-1-mediated MAPK signaling in the development of hepatic steatosis.

Public Health Relevance

The mitogen-activated protein kinases (MAPKs) and MAPK phosphatases regulate liver growth and metabolism. This Project studies the mechanisms through which nuclear calcium regulates the expression of MAPK phosphatases in the control of hepatic lipogenesis. This will include novel concepts of how excess nutrients influence MAPK-mediated lipogenic gene regulation through the actions of ER and nuclear stress. Together, these studies will provirie new insight into the undarlvina mechanisms of liver disease.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZDK1-GRB-8)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Yale University
New Haven
United States
Zip Code
Kuo, Ivana Y; Duong, Sophie L; Nguyen, Lily et al. (2016) Decreased Polycystin 2 Levels Result in Non-Renal Cardiac Dysfunction with Aging. PLoS One 11:e0153632
Wang, Simeng; Yang, Xiaoyong (2016) Inter-organ regulation of adipose tissue browning. Cell Mol Life Sci :
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
Lee, Hojin; Bennett, Anton M (2015) Identification of receptor protein tyrosine phosphatases (RPTPs) as regulators of receptor tyrosine kinases (RTKs) using an RPTP siRNA-RTK substrate screen. Methods Mol Biol 1233:111-20
Bindesbøll, Christian; Fan, Qiong; Nørgaard, Rikke C et al. (2015) Liver X receptor regulates hepatic nuclear O-GlcNAc signaling and carbohydrate responsive element-binding protein activity. J Lipid Res 56:771-85
Guerra, Mateus T; Nathanson, Michael H (2015) Calcium signaling and secretion in cholangiocytes. Pancreatology 15:S44-8
Singh, Jay Prakash; Zhang, Kaisi; Wu, Jing et al. (2015) O-GlcNAc signaling in cancer metabolism and epigenetics. Cancer Lett 356:244-50
Weerachayaphorn, Jittima; Amaya, Maria Jimena; Spirli, Carlo et al. (2015) Nuclear Factor, Erythroid 2-Like 2 Regulates Expression of Type 3 Inositol 1,4,5-Trisphosphate Receptor and Calcium Signaling in Cholangiocytes. Gastroenterology 149:211-222.e10
Ananthanarayanan, Meenakshisundaram; Banales, Jesus M; Guerra, Mateus T et al. (2015) Post-translational regulation of the type III inositol 1,4,5-trisphosphate receptor by miRNA-506. J Biol Chem 290:184-96
Lee, Hojin; Yi, Jae-Sung; Lawan, Ahmed et al. (2015) Mining the function of protein tyrosine phosphatases in health and disease. Semin Cell Dev Biol 37:66-72

Showing the most recent 10 out of 97 publications