The companion metabolic diseases, diabetes and obesity, are rapidly becoming the major health concern of western societies. The failure to accurately sense and respond to cellular metabolic status is a key factor in the pathogenesis of both diseases. We have shown that the protein kinase PAS kinase (PASK) is a sensor of cellular metabolic state that might play a role in obesity and diabetes. One of the most dramatic effects of PASK loss is protection from the highly deleterious ectopic lipid accumulation in liver typically observed in wild-type mice. The goal of this grant is to determine the role of PASK in regulating hepatic lipid metabolism in response to cellular metabolic state. This will be accomplished through the following specific aims: I. We will determine how PASK is regulated by both cellular and hormonal cues related to metabolic state. II. We will determine the mechanisms whereby PASK regulates hepatic lipid metabolism, focusing on regulation of SREBP-1, initially using a cultured cell model. III. We will determine whether PASK acts directly in the adult liver to affect transcription, lipid metabolism and glucose homeostasis using four new models of altered PASK expression.

Public Health Relevance

Obesity and diabetes are rapidly becoming the major health concern of western societies. A key aspect of both of these diseases is the inappropriate accumulation of fat or lipid in tissues such as the liver. We have shown that elimination of one specific gene, PAS kinase, prevents this liver lipid accumulation, at least under some situations. The purpose of this grant is to determine the mechanism(s) whereby PAS kinase regulates liver lipid accumulation and to extend these observations to directly assess the feasibility of PAS kinase as a therapeutic target in metabolic disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK071962-06
Application #
8109187
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Pawlyk, Aaron
Project Start
2005-09-01
Project End
2014-06-30
Budget Start
2011-07-01
Budget End
2012-06-30
Support Year
6
Fiscal Year
2011
Total Cost
$311,319
Indirect Cost
Name
University of Utah
Department
Biochemistry
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Wu, Xiaoying; Romero, Donna; Swiatek, Wojciech I et al. (2014) PAS kinase drives lipogenesis through SREBP-1 maturation. Cell Rep 8:242-55
Schell, John C; Olson, Kristofor A; Jiang, Lei et al. (2014) A role for the mitochondrial pyruvate carrier as a repressor of the Warburg effect and colon cancer cell growth. Mol Cell 56:400-13
Semache, Meriem; Zarrouki, Bader; Fontés, Ghislaine et al. (2013) Per-Arnt-Sim kinase regulates pancreatic duodenal homeobox-1 protein stability via phosphorylation of glycogen synthase kinase 3? in pancreatic ?-cells. J Biol Chem 288:24825-33
Orsak, Thomas; Smith, Tammy L; Eckert, Debbie et al. (2012) Revealing the allosterome: systematic identification of metabolite-protein interactions. Biochemistry 51:225-32
Cardon, Caleb M; Beck, Thomas; Hall, Michael N et al. (2012) PAS kinase promotes cell survival and growth through activation of Rho1. Sci Signal 5:ra9
Cardon, Caleb M; Rutter, Jared (2012) PAS kinase: integrating nutrient sensing with nutrient partitioning. Semin Cell Dev Biol 23:626-30
Bricker, Daniel K; Taylor, Eric B; Schell, John C et al. (2012) A mitochondrial pyruvate carrier required for pyruvate uptake in yeast, Drosophila, and humans. Science 337:96-100
Leclerc, I; Sun, G; Morris, C et al. (2011) AMP-activated protein kinase regulates glucagon secretion from mouse pancreatic alpha cells. Diabetologia 54:125-34
Semplici, Francesca; Vaxillaire, Martine; Fogarty, Sarah et al. (2011) Human mutation within Per-Arnt-Sim (PAS) domain-containing protein kinase (PASK) causes basal insulin hypersecretion. J Biol Chem 286:44005-14
Mbaya, E; Oulès, B; Caspersen, C et al. (2010) Calcium signalling-dependent mitochondrial dysfunction and bioenergetics regulation in respiratory chain Complex II deficiency. Cell Death Differ 17:1855-66

Showing the most recent 10 out of 29 publications