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Proteomic and Phosphoproteomic Signatures of Severe Alcoholic Hepatitis
Author(s) -
Hardesty Josiah,
Warner Jeffrey C.,
Warner Dennis C.,
Jacobs Jon,
McClain Craig C.,
Kirpich Irina A
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.473.4
Subject(s) - alcoholic hepatitis , alcoholic liver disease , transcription factor , hepatocyte nuclear factors , biology , hepatocyte nuclear factor 4 , signal transduction , medicine , gene , microbiology and biotechnology , nuclear receptor , biochemistry , cirrhosis
Background The increasing prevalence of alcoholic liver disease (ALD) presents a large global healthcare burden. Currently, no therapeutics are available and the mechanisms underlying ALD development and progression are not well understood. Alcoholic hepatitis (AH) is a severe stage of ALD with a high mortality. Thus, identifying new signaling pathways involved in AH development, as well as novel biomarkers of AH progression are of a great clinical importance. The current study was aimed to determine hepatic proteomic and phosphoproteomic signatures and impaired metabolic pathways in severe AH. Methods Liquid chromatography and tandem mass spectrometry analysis were performed to examine proteomic and phosphoproteomic changes in explanted liver tissues obtained from AH patients (n=6) and patients without ALD (controls, n=12). A Student's two‐tailed unpaired t‐test was used to determine statistical significance between the two groups. MetaCore ontology analyses (false‐discovery rate < 0.05) were performed to identify proteomic changes, transcription factors and metabolic/signaling pathways altered in AH patients. Results 3,288 peptides and 5,923 phospho‐peptides were significantly changed in AH liver samples compared to controls. The most diminished transcription factors in AH patients were hepatocyte nuclear factor 4‐alpha (HNF4a), hepatocyte nuclear factor 1‐alpha (HNF1a), and thyroid hormone receptor‐beta (THRb) as well as their target genes (45, 26, and 17 genes decreased in the networks, respectively). In contrast, the expression of transcription factors related to inflammation such as nuclear factor kappa B subunit 1 and 2 (NFkB1, NFkB2), as well as specificity protein 3 (SP3), were increased as were their target genes (9, 16, and 32 genes increased in each network, respectively). Further, the pathway involved in phagocytic bacterial clearance was significantly diminished in AH patients compared to control ( p =4.2e‐8), while the neutrophil extracellular trap pathway was elevated ( p =1.6e‐8). In addition, proteins involved in hepatocyte maturation ( p =1.4e‐6) and glutathione metabolism ( p =5.1e‐5) pathways were downregulated in AH patients. Conclusions Liver proteomic and phosphoproteomic analysis identified multiple alterations in transcriptional networks in AH patients characterized by diminished expression of transcription factors such as HNF4a, HNF1a, and THRb and elevation of NFkB1/2, and SP3. Further investigations are required to uncover new mechanisms in AH development and progression, as well as to identify novel biomarkers and therapeutic targets. Support or Funding Information NIH NIAAA RO1 AA024102NIH NIGMS P20 GM113226 This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .