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)
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Special Emphasis Panel (ZDK1-GRB-8)
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Yale University
New Haven
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