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

Christos Spanos; Elaina M. Maldonado; Ciarán P. Fisher; Petchpailin Leenutaphong; Ernesto Oviedo-Orta; David Windridge; Francisco J. Salguero; Alexandra Bermúdez-Fajardo; Mark E. Weeks; Caroline Evans; Bernard M. Corfe; Naila Rabbani; Paul J. Thornalley; Michael H. Miller; Huan Wang; John F Dillon; Alberto Quaglia; Anil Dhawan; Emer Fitzpatrick; J Bernadette Moore

doi:10.1186/s12953-018-0131-y

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

Christos Spanos, Elaina M. Maldonado, Ciarán P. Fisher, Petchpailin Leenutaphong, Ernesto Oviedo-Orta, David Windridge, Francisco J. Salguero, Alexandra Bermúdez-Fajardo, Mark E. Weeks, Caroline Evans, Bernard M. Corfe, Naila Rabbani, Paul J. Thornalley, Michael H. Miller, Huan Wang, John F Dillon, Alberto Quaglia, Anil Dhawan, Emer Fitzpatrick, J Bernadette Moore

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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.

Original language	English
Article number	4
Pages (from-to)	1-16
Number of pages	16
Journal	Proteome Science
Volume	16
DOIs	https://doi.org/10.1186/s12953-018-0131-y
Publication status	Published - 14 Feb 2018

Keywords

Glyoxalase
ITRAQ
Methylglyoxal
Non-alcoholic fatty liver disease
Proteomics

ASJC Scopus subject areas

Biochemistry
Molecular Biology

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10.1186/s12953-018-0131-yLicence: CC BY

Final Published VersionFinal published version, 1.91 MBLicence: CC BY

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Spanos, C., Maldonado, E. M., Fisher, C. P., Leenutaphong, P., Oviedo-Orta, E., Windridge, D., Salguero, F. J., Bermúdez-Fajardo, A., Weeks, M. E., Evans, C., Corfe, B. M., Rabbani, N., Thornalley, P. J., Miller, M. H., Wang, H., Dillon, J. F., Quaglia, A., Dhawan, A., Fitzpatrick, E., & Bernadette Moore, J. (2018). Proteomic identification and characterization of hepatic glyoxalase 1 dysregulation in non-alcoholic fatty liver disease. Proteome Science, 16, 1-16. Article 4. https://doi.org/10.1186/s12953-018-0131-y

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

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 = "Glyoxalase, ITRAQ, Methylglyoxal, Non-alcoholic fatty liver disease, Proteomics",

author = "Christos Spanos and Maldonado, {Elaina M.} and Fisher, {Ciar{\'a}n P.} and Petchpailin Leenutaphong and Ernesto Oviedo-Orta and David Windridge and Salguero, {Francisco J.} and Alexandra Berm{\'u}dez-Fajardo and Weeks, {Mark E.} and Caroline Evans and Corfe, {Bernard M.} and Naila Rabbani and Thornalley, {Paul J.} and Miller, {Michael H.} and Huan Wang and Dillon, {John F} and Alberto Quaglia and Anil Dhawan and Emer Fitzpatrick and {Bernadette Moore}, J",

year = "2018",

month = feb,

day = "14",

doi = "10.1186/s12953-018-0131-y",

language = "English",

volume = "16",

pages = "1--16",

journal = "Proteome Science",

issn = "1477-5956",

publisher = "Springer Verlag",

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Spanos, C, Maldonado, EM, Fisher, CP, Leenutaphong, P, Oviedo-Orta, E, Windridge, D, Salguero, FJ, Bermúdez-Fajardo, A, Weeks, ME, Evans, C, Corfe, BM, Rabbani, N, Thornalley, PJ, Miller, MH, Wang, H , Dillon, JF, Quaglia, A, Dhawan, A, Fitzpatrick, E & Bernadette Moore, J 2018, 'Proteomic identification and characterization of hepatic glyoxalase 1 dysregulation in non-alcoholic fatty liver disease', Proteome Science, vol. 16, 4, pp. 1-16. https://doi.org/10.1186/s12953-018-0131-y

TY - JOUR

T1 - Proteomic identification and characterization of hepatic glyoxalase 1 dysregulation in non-alcoholic fatty liver disease

AU - Spanos, Christos

AU - Maldonado, Elaina M.

AU - Fisher, Ciarán P.

AU - Leenutaphong, Petchpailin

AU - Oviedo-Orta, Ernesto

AU - Windridge, David

AU - Salguero, Francisco J.

AU - Bermúdez-Fajardo, Alexandra

AU - Weeks, Mark E.

AU - Evans, Caroline

AU - Corfe, Bernard M.

AU - Rabbani, Naila

AU - Thornalley, Paul J.

AU - Miller, Michael H.

AU - Wang, Huan

AU - Dillon, John F

AU - Quaglia, Alberto

AU - Dhawan, Anil

AU - Fitzpatrick, Emer

AU - Bernadette Moore, J

PY - 2018/2/14

Y1 - 2018/2/14

N2 - 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.

AB - 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.

KW - Glyoxalase

KW - ITRAQ

KW - Methylglyoxal

KW - Non-alcoholic fatty liver disease

KW - Proteomics

UR - http://www.scopus.com/inward/record.url?scp=85042102015&partnerID=8YFLogxK

U2 - 10.1186/s12953-018-0131-y

DO - 10.1186/s12953-018-0131-y

M3 - Article

C2 - 29456458

SN - 1477-5956

VL - 16

SP - 1

EP - 16

JO - Proteome Science

JF - Proteome Science

M1 - 4

ER -

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

Abstract

Keywords

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

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