The objective of the studies is to define novel molecular pathways that regulate hepatocellular injury and death. Employing models of toxic liver injury our underlying hypothesis has been that cell death is not the passive result of the biochemical effects of the toxin but an active process regulated by cell signaling pathways. Studies have focused on how toxic injury alters hepatocyte responses to tumor necrosis factor-? (TNF) and reactive oxygen species (ROS) which are two central mediators of liver injury. Our investigations have delineated the critical involvement of c-Jun N-terminal kinase (JNK) signaling in hepatocyte death from TNF and ROS and in toxic liver injury, and JNK overactivation has been established as a central mechanism of other forms of hepatic injury. However, the mechanisms by which JNK regulates hepatocyte death after injury remain unclear and are complicated by the fact that JNK isoforms function to alternatively promote or resist cell death depending on the nature of the injury. In contrast to prior investigations that focused on JNK's direct involvement in cell death pathways, our studies have identified stathmin and glutaminase as novel JNK substrates and indicate that JNK2 regulation of cell death is mediated through effects on common cellular functions such as microtubule stabilization, glutamine metabolism and autophagy. Based on these and other preliminary studies, our central hypothesis is that JNK2 signaling regulates hepatocyte injury and death predominantly by altering basic cellular processes including cytoskeletal dynamics and metabolism rather than through direct effects on cell death pathway components. We will test this hypothesis by delineating the mechanisms by which JNK regulates hepatocellular injury and death in studies contained in three Specific Aims. First, we will test the hypothesis that JNK2-dependent phosphorylation of stathmin stabilizes microtubules to block hepatocyte death from ROS and TNF. Second, we will test the hypothesis that JNK2 promotes hepatocellular injury by decreasing levels of the glutamine-metabolizing enzyme glutaminase and ammonia generation, thereby reducing autophagy and leading to cell death. Third, we will test the hypothesis that autophagy protects against liver injury through the mobilization of fatty acids that maintains cellular energy homeostasis and inhibits activation of the mitochondrial death pathway. These studies will delineate novel paradigms by which JNK regulation of common cellular pathways leads to profound effects on the sensitivity of hepatocytes to death after cellular injury. The ultimate goal of these investigations is to better understand how hepatocytes are injured and die in order to prevent this process and the development of hepatic failure in human liver diseases.

Public Health Relevance

Acute and chronic liver failure constitutes one of the leading causes of death in the United States. Whatever the etiology of the underlying liver disease, the ultimate cause of hepatic failure is the injury and death of hepatocytes to the extent that there i insufficient liver function for patient survival. It is the objective of this proposal to increase ur understanding of the molecular mechanisms of hepatocyte injury and death in order that new approaches to the prevention of liver failure can be developed.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK044234-21
Application #
8702142
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Doo, Edward
Project Start
1992-04-01
Project End
2017-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
21
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Bronx
State
NY
Country
United States
Zip Code
10461
Singh, Saurav; Grabner, Alexander; Yanucil, Christopher et al. (2016) Fibroblast growth factor 23 directly targets hepatocytes to promote inflammation in chronic kidney disease. Kidney Int 90:985-996
Ilyas, Ghulam; Zhao, Enpeng; Liu, Kun et al. (2016) Macrophage autophagy limits acute toxic liver injury in mice through down regulation of interleukin-1β. J Hepatol 64:118-27
(2016) Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 12:1-222
Liu, Kun; Zhao, Enpeng; Ilyas, Ghulam et al. (2015) Impaired macrophage autophagy increases the immune response in obese mice by promoting proinflammatory macrophage polarization. Autophagy 11:271-84
Schattenberg, Jörn M; Czaja, Mark J (2014) Regulation of the effects of CYP2E1-induced oxidative stress by JNK signaling. Redox Biol 3:7-15
Zhao, Enpeng; Amir, Muhammad; Lin, Yu et al. (2014) Stathmin mediates hepatocyte resistance to death from oxidative stress by down regulating JNK. PLoS One 9:e109750
Fucho, Raquel; Martínez, Laura; Baulies, Anna et al. (2014) ASMase regulates autophagy and lysosomal membrane permeabilization and its inhibition prevents early stage non-alcoholic steatohepatitis. J Hepatol 61:1126-34
Liu, K; Czaja, M J (2013) Regulation of lipid stores and metabolism by lipophagy. Cell Death Differ 20:3-11
Amir, M; Zhao, E; Fontana, L et al. (2013) Inhibition of hepatocyte autophagy increases tumor necrosis factor-dependent liver injury by promoting caspase-8 activation. Cell Death Differ 20:878-87
Czaja, Mark J; Ding, Wen-Xing; Donohue Jr, Terrence M et al. (2013) Functions of autophagy in normal and diseased liver. Autophagy 9:1131-58

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