One of every three American adults is obese and is afflicted with some form of non-alcoholic fatty liver disease (NAFLD). The majority of obese individuals will have steatosis (fatty liver), but only about 20% will have the more serious condition of steatohepatitis (fatty liver with inflammation and liver injury). There is still no FDA- approved therapy for any stage of NAFLD. Therefore, it is critical that we understand the multiple factors that promote progression from steatosis to steatohepatitis in NAFLD. Our previous studies have shown that consumption of arsenic-contaminated drinking water is an important risk factor for progression of NAFLD. Preliminary proteomic analysis demonstrated that the abundance of a number of proteins that are controlled at the transcriptional level by HNF-4a was decreased in the livers of mice with arsenic-enhanced NAFLD. Mechanistic studies showed that the expression of this zinc finger transcription factor was not altered, but that its DNA binding activity was inhibited at the post-translational level. HNF-4a is known to be regulated by post- translational modifications (PTMs), and arsenic has the potential to affect zinc binding, cysteine oxidation, arginine methylation and lysine acetylation. Very little is known about how PTMs of HNF-4a are regulated, or how disruption of these regulatory processes contributes to liver disease. To follow up on these important findings, the objective of the current proposal is to delineate the mechanisms by which environmental arsenic exposure promotes the progression from steatosis to steatohepatitis in mice fed a Western-style diet that is high in saturated fat. The central hypothesis to be tested is that alterations in HNF-4a-mediated gene expression induced by arsenic play a critical role in the progression of NAFLD from steatosis to steatohepatitis in this model. This hypothesis will be tested in three Specific Aims. First, we will define the specific molecular interactions of arsenic with the zinc finger domain of HNF-4a. Second, we will analyze the mechanisms by which arsenic affects PTMs of HNF-4a, and how these changes translate into altered DNA binding activity and transactivation potential. Third, we will define the post-translational modifications of hepatic HNF-4a in mice fed a high fat diet and exposed to arsenic-contaminated drinking water, and relate these changes to the occupancy of HNF-4a-response elements in genes involved in lipid metabolism and inflammation. This model of inflammatory liver injury is relevant to the United States population, where high fat diets are common and arsenic exposure levels are typically below the threshold for overt hepatotoxicity. The new information obtained from these studies will delineate pathways that are altered by arsenic and that are important in the etiology of NAFLD.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Exploratory Grants (P20)
Project #
1P20GM113226-01
Application #
8813884
Study Section
Special Emphasis Panel (ZGM1-TWD-A (C1))
Project Start
2016-06-10
Project End
2021-03-31
Budget Start
2014-12-01
Budget End
2015-11-30
Support Year
1
Fiscal Year
2016
Total Cost
$184,680
Indirect Cost
$64,680
Name
University of Louisville
Department
Type
DUNS #
057588857
City
Louisville
State
KY
Country
United States
Zip Code
40208
Lang, Anna L; Beier, Juliane I (2018) Interaction of volatile organic compounds and underlying liver disease: a new paradigm for risk. Biol Chem 399:1237-1248
Beier, Juliane I; Banales, Jesus M (2018) Pyroptosis: An inflammatory link between NAFLD and NASH with potential therapeutic implications. J Hepatol :
Shao, Tuo; Zhao, Cuiqing; Li, Fengyuan et al. (2018) Intestinal HIF-1? deletion exacerbates alcoholic liver disease by inducing intestinal dysbiosis and barrier dysfunction. J Hepatol 69:886-895
Poole, Lauren G; Beier, Juliane I; Torres-Gonzales, Edilson et al. (2018) Chronic + binge alcohol exposure promotes inflammation and alters airway mechanics in the lung. Alcohol :
Hardesty, Josiah E; Al-Eryani, Laila; Wahlang, Banrida et al. (2018) Epidermal Growth Factor Receptor Signaling Disruption by Endocrine and Metabolic Disrupting Chemicals. Toxicol Sci 162:622-634
Cui, Guozhen; Martin, Robert C; Liu, Xingkai et al. (2018) Serological biomarkers associate ultrasound characteristics of steatohepatitis in mice with liver cancer. Nutr Metab (Lond) 15:71
Cui, Guozhen; Martin, Robert C; Jin, Hang et al. (2018) Up-regulation of FGF15/19 signaling promotes hepatocellular carcinoma in the background of fatty liver. J Exp Clin Cancer Res 37:136
Zheng, Yuxuan; Ritzenthaler, Jeffrey D; Burke, Tom J et al. (2018) Age-dependent oxidation of extracellular cysteine/cystine redox state (Eh(Cys/CySS)) in mouse lung fibroblasts is mediated by a decline in Slc7a11 expression. Free Radic Biol Med 118:13-22
Hein, David W; Zhang, Xiaoyan; Doll, Mark A (2018) Role of N-acetyltransferase 2 acetylation polymorphism in 4, 4'-methylene bis (2-chloroaniline) biotransformation. Toxicol Lett 283:100-105
Hein, David W; Fakis, Giannoulis; Boukouvala, Sotiria (2018) Functional expression of human arylamine N-acetyltransferase NAT1*10 and NAT1*11 alleles: a mini review. Pharmacogenet Genomics 28:238-244

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