Proteomic identification and characterization of hepatic glyoxalase 1 dysregulation in non-alcoholic fatty liver disease

Spanos, Christos, Maldonado, Elaina M., Fisher, Ciarán P., Leenutaphong, Petchpailin, Oviedo-Orta, Ernesto, Windridge, David ORCID: https://orcid.org/0000-0001-5507-8516, Salguero, Francisco J., Bermúdez-Fajardo, Alexandra, Weeks, Mark E., Evans, Caroline, Corfe, Bernard M., Rabbani, Naila, Thornalley, Paul J., Miller, Michael H., Wang, Huan, Dillon, John F., Quaglia, Alberto, Dhawan, Anil, Fitzpatrick, Emer and Bernadette Moore, J. (2018) Proteomic identification and characterization of hepatic glyoxalase 1 dysregulation in non-alcoholic fatty liver disease. Proteome Science, 16 (1). ISSN 1477-5956 (doi:10.1186/s12953-018-0131-y)

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Abstract

Background: Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide. However, its
molecular pathogenesis is incompletely characterized and clinical biomarkers remain scarce. The aims of these
experiments were to identify and characterize liver protein alterations in an animal model of early, diet-related,
liver injury and to assess novel candidate biomarkers in NAFLD patients.
Methods: Liver membrane and cytosolic protein fractions from high fat fed apolipoprotein E knockout (ApoE−/−)
animals were analyzed by quantitative proteomics, utilizing isobaric tags for relative and absolute quantitation
(iTRAQ) combined with nano-liquid chromatography and tandem mass spectrometry (nLC-MS/MS). Differential
protein expression was confirmed independently by immunoblotting and immunohistochemistry in both murine
tissue and biopsies from paediatric NAFLD patients. Candidate biomarkers were analyzed by enzyme-linked
immunosorbent assay in serum from adult NAFLD patients.
Results: Through proteomic profiling, we identified decreased expression of hepatic glyoxalase 1 (GLO1) in a
murine model. GLO1 protein expression was also found altered in tissue biopsies from paediatric NAFLD patients. In
vitro experiments demonstrated that, in response to lipid loading in hepatocytes, GLO1 is first hyperacetylated then
ubiquitinated and degraded, leading to an increase in reactive methylglyoxal. In a cohort of 59 biopsy-confirmed adult
NAFLD patients, increased serum levels of the primary methylglyoxal-derived advanced glycation endproduct,
hydroimidazolone (MG-H1) were significantly correlated with body mass index (r = 0.520, p < 0.0001).
Conclusion: Collectively these results demonstrate the dysregulation of GLO1 in NAFLD and implicate the
acetylation-ubquitination degradation pathway as the functional mechanism. Further investigation of the role
of GLO1 in the molecular pathogenesis of NAFLD is warranted.
Keywords: Non-alcoholic fatty liver disease, Glyoxalase, Methylglyoxal, Proteomics, iTRAQ

Item Type: Article
Research Areas: A. > School of Science and Technology > Computer Science
Item ID: 23671
Notes on copyright: © The Author(s). 2018
Useful Links:
Depositing User: David Windridge
Date Deposited: 27 Feb 2018 15:37
Last Modified: 04 Apr 2019 05:08
URI: https://eprints.mdx.ac.uk/id/eprint/23671

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