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

Spanos, C, Maldonado, Elaina, Fisher, C, Leenutaphong, P, Oviedo-Orta, E, Windridge, David, Salguero Bodes, Francisco, Bermúdez-Fajardo, A, Weeks, M, Evans, C , Corfe, B, Rabbani, N, Thornalley, P, Miller, M, Wang, H, Dillon, J, Quaglia, A, Dhawan, A, Fitzpatrick, E and Moore, J (2018) Proteomic identification and characterization of hepatic glyoxalase 1 dysregulation in non-alcoholic fatty liver disease Proteome Science.

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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 NAFLD 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 of NAFLD. 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 ubiquitinylated 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). Conclusions: 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.

Item Type: Article
Divisions : Faculty of Health and Medical Sciences > School of Veterinary Medicine
Authors :
NameEmailORCID
Spanos, CUNSPECIFIEDUNSPECIFIED
Maldonado, Elainae.m.maldonado@surrey.ac.ukUNSPECIFIED
Fisher, CUNSPECIFIEDUNSPECIFIED
Leenutaphong, PUNSPECIFIEDUNSPECIFIED
Oviedo-Orta, EUNSPECIFIEDUNSPECIFIED
Windridge, DavidD.Windridge@surrey.ac.ukUNSPECIFIED
Salguero Bodes, Franciscof.salguerobodes@surrey.ac.ukUNSPECIFIED
Bermúdez-Fajardo, AUNSPECIFIEDUNSPECIFIED
Weeks, MUNSPECIFIEDUNSPECIFIED
Evans, CUNSPECIFIEDUNSPECIFIED
Corfe, BUNSPECIFIEDUNSPECIFIED
Rabbani, NUNSPECIFIEDUNSPECIFIED
Thornalley, PUNSPECIFIEDUNSPECIFIED
Miller, MUNSPECIFIEDUNSPECIFIED
Wang, HUNSPECIFIEDUNSPECIFIED
Dillon, JUNSPECIFIEDUNSPECIFIED
Quaglia, AUNSPECIFIEDUNSPECIFIED
Dhawan, AUNSPECIFIEDUNSPECIFIED
Fitzpatrick, EUNSPECIFIEDUNSPECIFIED
Moore, JUNSPECIFIEDUNSPECIFIED
Date : 6 May 2018
Copyright Disclaimer : Copyright 2018 The Author(s) and published under the Creative Commons Attribution License 4.0.
Uncontrolled Keywords : Non-alcoholic fatty liver disease, glyoxalase, methylglyoxal, proteomics, iTRAQ
Depositing User : Melanie Hughes
Date Deposited : 06 Feb 2018 09:53
Last Modified : 06 Feb 2018 09:59
URI: http://epubs.surrey.ac.uk/id/eprint/845749

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