In nonalcoholic fatty liver disease (NAFLD) the cellular signals that initiate hepatocyte lipid accumulation and progression from benign steatosis to hepatocyte injury and chronic liver disease are unknown. Both experimental and human NAFLD are associated with hepatic oxidative stress along with overexpression of prooxidant cytochrome P450 (CYP) enzymes. Our general hypothesis has been that oxidative stress in this disease alters cell signaling cascades that promote the development of hepatocyte injury. Investigations over the past funding period have defined effects of oxidative stress on mitogen-activated protein kinases (MARK) that regulate hepatocyte injury and death. Other studies have demonstrated that oxidative stress generated by CYP2E1 overexpression alters hepatic metabolism including insulin sensitivity and lipid accumulation. Based on these studies and additional preliminary data, our central hypothesis is that overactivation of MAPK signaling by chronic oxidative stress is a critical mechanism in the development of both hepatic steatosis and injury. We propose to test this hypothesis with studies in hepatocyte and in vivo models of steatosis and oxidative stress that are contained in four specific aims. First, we will test the hypothesis that Bim down regulation is the mechanism by which CYP2E1-overexpressing hepatocytes resist death from oxidant stress. Second, we will test the hypothesis that CYP2E1-overexpressing hepatocytes are susceptible to proapoptotic JNK/AP- 1 overactivation because of redox-dependent phosphatase inhibition. Third, we will test the hypothesis that insulin resistance mediated by oxidant-induced JNK signaling promotes hepatocyte steatosis. Fourth, we will test the hypothesis that oxidative stress in the setting of lipid accumulation stimulates JNK mediated cell death from endoplasmic reticulum stress. The ultimate goal of these investigations is to better understand the basic cellular mechanisms that lead to the development of steatosis and steatohepatitis in order to design new strategies to prevent and treat human NAFLD. Relevance to public health: NAFLD is a very prevalent liver disease which has no known treatment. Attempts to understand the mechanisms of lipid accumulation and liver injury in this disease are important to the development of new strategies for the prevention and treatment of NAFLD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK061498-10
Application #
8112431
Study Section
Special Emphasis Panel (ZRG1-DIG-F (02))
Program Officer
Doo, Edward
Project Start
2002-05-15
Project End
2012-06-30
Budget Start
2011-07-01
Budget End
2012-06-30
Support Year
10
Fiscal Year
2011
Total Cost
$326,857
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
110521739
City
Bronx
State
NY
Country
United States
Zip Code
10461
Klionsky, Daniel J (see original citation for additional authors) (2016) Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 12:1-222
Lalazar, Gadi; Ilyas, Ghulam; Malik, Shoaib Ahmad et al. (2016) Autophagy confers resistance to lipopolysaccharide-induced mouse hepatocyte injury. Am J Physiol Gastrointest Liver Physiol 311:G377-86
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
Czaja, Mark J (2016) Function of Autophagy in Nonalcoholic Fatty Liver Disease. Dig Dis Sci 61:1304-13
Cingolani, Francesca; Czaja, Mark J (2016) Regulation and Functions of Autophagic Lipolysis. Trends Endocrinol Metab 27:696-705
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
Czaja, Mark J (2015) A new mechanism of lipotoxicity: Calcium channel blockers as a treatment for nonalcoholic steatohepatitis? Hepatology 62:312-4
Schattenberg, Jörn M; Czaja, Mark J (2014) Regulation of the effects of CYP2E1-induced oxidative stress by JNK signaling. Redox Biol 3:7-15
Huebener, Peter; Gwak, Geum-Youn; Pradere, Jean-Philippe et al. (2014) High-mobility group box 1 is dispensable for autophagy, mitochondrial quality control, and organ function in vivo. Cell Metab 19:539-47
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

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