Nonalcoholic fatty liver disease (NAFLD) is a multifactorial clinicopathologic condition characterized by marked lipid accumulation in hepatocytes. The prevalence ranges from 10-24% across a spectrum of populations with upwards to 58% of obese adults and 53% of obese children affected by this disorder. The mechanisms underlying the transition of this disease to the more advanced stage, (NASH), characterized by hepatosteatosis, hepatocyte death and fibrosis remain to be elucidated although oxidative stress is proposed to play a central role in this progression. Oxidative stress is characterized by the production of reactive oxygen species (ROS) which initiate lipid peroxidation giving rise to bioactive aldehydic products of lipid peroxidation including 4-hydroxy-2-nonenal (4-HNE) and 4-oxononenal (4-ONE). It is our working hypothesis that specific protein modifications by 4-HNE and 4-ONE play important roles in the pathogenesis of NASH. This hypothesis will be tested by systematic experiments proposed in three specific aims using a mouse model of dietary-induced fatty liver. Experiments in Aim 1 will establish mechanistic relationships of documented biochemical and metabolic hallmarks of NAFLD and NASH with hepatic oxidative stress to delineate the ability of 4-HNE and 4-ONE to orchestrate the """"""""second hit"""""""". Parameters to be characterized which emerge during the progression of NAFLD and NASH include hepatic histopathology, insulin sensitivity, dysregulation of lipid homoeostasis, increased production of TNF-a, decreases in adiponectin, the overproduction of proinflammatory cytokines as well as inflammation and fibrosis. Experiments in Aim 2 will identify hepatic proteins modified by 4-HNE and 4-ONE with the goal of identifying mechanistic links with initiation and progression of NASH. Experiments are proposed using the candidate proteins, long-chain acyl CoA dehydrogenase and the ER stress modulator GRP78 to evaluate the functional consequences of protein modification by 4-HNE and 4-ONE produced in association with NASH. Novel studies in Aim 3 will employ proteomic approaches to evaluate the hepatoprotective mechanisms of taurine supplementation in arresting NAFLD and NASH by restoration of ER stress response and protection against TNF-alpha-induced cell death. These proposed experiments will provide new insight into the pathomechanisms of NAFLD and potential therapeutic approaches to the treatment of this liver disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK074487-05
Application #
8123104
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Doo, Edward
Project Start
2007-09-01
Project End
2013-07-31
Budget Start
2011-08-01
Budget End
2013-07-31
Support Year
5
Fiscal Year
2011
Total Cost
$300,742
Indirect Cost
Name
University of Colorado Denver
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
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Smathers, Rebecca L; Galligan, James J; Shearn, Colin T et al. (2013) Susceptibility of L-FABP-/- mice to oxidative stress in early-stage alcoholic liver. J Lipid Res 54:1335-45
Shearn, C T; Smathers, R L; Backos, D S et al. (2013) Increased carbonylation of the lipid phosphatase PTEN contributes to Akt2 activation in a murine model of early alcohol-induced steatosis. Free Radic Biol Med 65:680-92
Basseri, Sana; Lhoták, Sárka; Fullerton, Morgan D et al. (2013) Loss of TDAG51 results in mature-onset obesity, hepatic steatosis, and insulin resistance by regulating lipogenesis. Diabetes 62:158-69
Shearn, Colin T; Smathers, Rebecca L; Jiang, Hua et al. (2013) Increased dietary fat contributes to dysregulation of the LKB1/AMPK pathway and increased damage in a mouse model of early-stage ethanol-mediated steatosis. J Nutr Biochem 24:1436-45
Fritz, Kristofer S; Green, Michelle F; Petersen, Dennis R et al. (2013) Ethanol metabolism modifies hepatic protein acylation in mice. PLoS One 8:e75868
Fritz, Kristofer S; Petersen, Dennis R (2013) An overview of the chemistry and biology of reactive aldehydes. Free Radic Biol Med 59:85-91
Galligan, James J; Petersen, Dennis R (2012) The human protein disulfide isomerase gene family. Hum Genomics 6:6
Shearn, Colin T; Reigan, Philip; Petersen, Dennis R (2012) Inhibition of hydrogen peroxide signaling by 4-hydroxynonenal due to differential regulation of Akt1 and Akt2 contributes to decreases in cell survival and proliferation in hepatocellular carcinoma cells. Free Radic Biol Med 53:1-11

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