Nonalcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disease worldwide, yet its pathogenesis remains poorly understood. Impaired mitochondrial function is largely thought to be a core abnormality responsible for disease progression in this condition. The central question extant is what events link excessive lipid accumulation in liver cells to mitochondrial dysfunction. Thus, the overall objective of this proposal is to define the cellular and molecular mechanisms contributing to mitochondrial dysfunction and disease progression in NAFLD. Based on extensive preliminary data, we propose the novel CENTRAL HYPOTHESIS that excessive free fatty acids accumulation in the liver results in impaired mitochondrial function and NAFLD progression by triggering lysosomal permeabilization via regulation of the Bcl-2 family members We will now employ current and complementary, molecular, biochemical and cell biological approaches to further explore the lysosomal - mitochondrial axis in NAFLD. Our proposal has three SPECIFIC AIMS. FIRST, we will identify and manipulate novel intracellular targets that initiate lysosomal permeabilization in in-vitro and in-vivo models of NAFLD as well as human specimens of NAFLD and control individuals. SECOND, we will molecularly define the lysosomal - mitochondrial axis in models of NAFLD and cell free systems. FINALLY, we will determine if inhibition of lysosomal permeabilization and cathepsin B activation prevent liver injury and fibrosis in an in-vitro tissue model and in-vivo dietary murine models of NAFLD. The proposal is innovative technically and conceptually as it tests new concepts for lipid induced hepatotoxicity using sophisticated technologies. Moreover, because lipotoxicity as a result of over-accumulation of free fatty acids in non-adipose tissues has been implicated in the pathogenesis of other human liver diseases including chronic hepatitis C infection, alcoholic steatohepatitis and hemochromatosis, as well as other diseases such as type II diabetes and obesity associated heart disease the results of this proposal may not only bring new insights to the mechanisms underlying these conditions, but also could translate into new therapeutic strategies to treat them (e.g. the use of pharmacological Bax or cathepsin B inhibitors).

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
3R01DK076852-03S1
Application #
7777089
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Doo, Edward
Project Start
2007-03-01
Project End
2012-01-31
Budget Start
2009-02-01
Budget End
2010-01-31
Support Year
3
Fiscal Year
2009
Total Cost
$1,545
Indirect Cost
Name
Cleveland Clinic Lerner
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
Wree, Alexander; McGeough, Matthew D; Inzaugarat, Maria Eugenia et al. (2017) NLRP3 inflammasome driven liver injury and fibrosis: Roles of IL-17 and TNF in mice. Hepatology :
Alkhouri, Naim; Feldstein, Ariel E (2016) Noninvasive diagnosis of nonalcoholic fatty liver disease: Are we there yet? Metabolism 65:1087-95
Wree, A; Johnson, C D; Font-Burgada, J et al. (2015) Hepatocyte-specific Bid depletion reduces tumor development by suppressing inflammation-related compensatory proliferation. Cell Death Differ 22:1985-94
Navarro, Laura A; Wree, Alexander; Povero, Davide et al. (2015) Arginase 2 deficiency results in spontaneous steatohepatitis: a novel link between innate immune activation and hepatic de novo lipogenesis. J Hepatol 62:412-20
Lazic, Milos; Eguchi, Akiko; Berk, Michael P et al. (2014) Differential regulation of inflammation and apoptosis in Fas-resistant hepatocyte-specific Bid-deficient mice. J Hepatol 61:107-15
Eguchi, Akiko; Wree, Alexander; Feldstein, Ariel E (2014) Biomarkers of liver cell death. J Hepatol 60:1063-74
Wree, Alexander; Eguchi, Akiko; McGeough, Matthew D et al. (2014) NLRP3 inflammasome activation results in hepatocyte pyroptosis, liver inflammation, and fibrosis in mice. Hepatology 59:898-910
Wree, Alexander; McGeough, Matthew D; Peña, Carla A et al. (2014) NLRP3 inflammasome activation is required for fibrosis development in NAFLD. J Mol Med (Berl) 92:1069-82
Lazic, Milos; Inzaugarat, Maria Eugenia; Povero, Davide et al. (2014) Reduced dietary omega-6 to omega-3 fatty acid ratio and 12/15-lipoxygenase deficiency are protective against chronic high fat diet-induced steatohepatitis. PLoS One 9:e107658
Cusi, Kenneth; Chang, Zhi; Harrison, Steve et al. (2014) Limited value of plasma cytokeratin-18 as a biomarker for NASH and fibrosis in patients with non-alcoholic fatty liver disease. J Hepatol 60:167-74

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