Uncovering a Predictive Molecular Signature for the Onset of NASH-Related Fibrosis in a Translational NASH Mouse Model

Arianne van Koppen, Lars Verschuren, Anita M. van den Hoek, Joanne Verheij, Martine C. Morrison, Kelvin Li, Hiroshi Nagabukuro, Adalberto Costessi, Martien P. M. Caspers, Tim J. van den Broek, John Sagartz, Cornelis Kluft, Carine Beysen, Claire Emson, Alain J. van Gool, Roel Goldschmeding, Reinout Stoop, Ivana Bobeldijk-Pastorova, Scott M. Turner, Guido Hanauer & 1 others Roeland Hanemaaijer

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Background & Aims The incidence of nonalcoholic steatohepatitis (NASH) is increasing. The pathophysiological mechanisms of NASH and the sequence of events leading to hepatic fibrosis are incompletely understood. The aim of this study was to gain insight into the dynamics of key molecular processes involved in NASH and to rank early markers for hepatic fibrosis. Methods A time-course study in low-density lipoprotein–receptor knockout. Leiden mice on a high-fat diet was performed to identify the temporal dynamics of key processes contributing to NASH and fibrosis. An integrative systems biology approach was used to elucidate candidate markers linked to the active fibrosis process by combining transcriptomics, dynamic proteomics, and histopathology. The translational value of these findings were confirmed using human NASH data sets. Results High-fat-diet feeding resulted in obesity, hyperlipidemia, insulin resistance, and NASH with fibrosis in a time-dependent manner. Temporal dynamics of key molecular processes involved in the development of NASH were identified, including lipid metabolism, inflammation, oxidative stress, and fibrosis. A data-integrative approach enabled identification of the active fibrotic process preceding histopathologic detection using a novel molecular fibrosis signature. Human studies were used to identify overlap of genes and processes and to perform a network biology-based prioritization to rank top candidate markers representing the early manifestation of fibrosis. Conclusions An early predictive molecular signature was identified that marked the active profibrotic process before histopathologic fibrosis becomes manifest. Early detection of the onset of NASH and fibrosis enables identification of novel blood-based biomarkers to stratify patients at risk, development of new therapeutics, and help shorten (pre)clinical experimental time frames.
Original languageEnglish
Pages (from-to)83-98.e10
JournalCellular and Molecular Gastroenterology and Hepatology
Volume5
Issue number1
DOIs
Publication statusPublished - 2018
Externally publishedYes

Cite this

van Koppen, Arianne ; Verschuren, Lars ; van den Hoek, Anita M. ; Verheij, Joanne ; Morrison, Martine C. ; Li, Kelvin ; Nagabukuro, Hiroshi ; Costessi, Adalberto ; Caspers, Martien P. M. ; van den Broek, Tim J. ; Sagartz, John ; Kluft, Cornelis ; Beysen, Carine ; Emson, Claire ; van Gool, Alain J. ; Goldschmeding, Roel ; Stoop, Reinout ; Bobeldijk-Pastorova, Ivana ; Turner, Scott M. ; Hanauer, Guido ; Hanemaaijer, Roeland. / Uncovering a Predictive Molecular Signature for the Onset of NASH-Related Fibrosis in a Translational NASH Mouse Model. In: Cellular and Molecular Gastroenterology and Hepatology. 2018 ; Vol. 5, No. 1. pp. 83-98.e10.
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title = "Uncovering a Predictive Molecular Signature for the Onset of NASH-Related Fibrosis in a Translational NASH Mouse Model",
abstract = "Background & Aims The incidence of nonalcoholic steatohepatitis (NASH) is increasing. The pathophysiological mechanisms of NASH and the sequence of events leading to hepatic fibrosis are incompletely understood. The aim of this study was to gain insight into the dynamics of key molecular processes involved in NASH and to rank early markers for hepatic fibrosis. Methods A time-course study in low-density lipoprotein–receptor knockout. Leiden mice on a high-fat diet was performed to identify the temporal dynamics of key processes contributing to NASH and fibrosis. An integrative systems biology approach was used to elucidate candidate markers linked to the active fibrosis process by combining transcriptomics, dynamic proteomics, and histopathology. The translational value of these findings were confirmed using human NASH data sets. Results High-fat-diet feeding resulted in obesity, hyperlipidemia, insulin resistance, and NASH with fibrosis in a time-dependent manner. Temporal dynamics of key molecular processes involved in the development of NASH were identified, including lipid metabolism, inflammation, oxidative stress, and fibrosis. A data-integrative approach enabled identification of the active fibrotic process preceding histopathologic detection using a novel molecular fibrosis signature. Human studies were used to identify overlap of genes and processes and to perform a network biology-based prioritization to rank top candidate markers representing the early manifestation of fibrosis. Conclusions An early predictive molecular signature was identified that marked the active profibrotic process before histopathologic fibrosis becomes manifest. Early detection of the onset of NASH and fibrosis enables identification of novel blood-based biomarkers to stratify patients at risk, development of new therapeutics, and help shorten (pre)clinical experimental time frames.",
author = "{van Koppen}, Arianne and Lars Verschuren and {van den Hoek}, {Anita M.} and Joanne Verheij and Morrison, {Martine C.} and Kelvin Li and Hiroshi Nagabukuro and Adalberto Costessi and Caspers, {Martien P. M.} and {van den Broek}, {Tim J.} and John Sagartz and Cornelis Kluft and Carine Beysen and Claire Emson and {van Gool}, {Alain J.} and Roel Goldschmeding and Reinout Stoop and Ivana Bobeldijk-Pastorova and Turner, {Scott M.} and Guido Hanauer and Roeland Hanemaaijer",
year = "2018",
doi = "10.1016/j.jcmgh.2017.10.001",
language = "English",
volume = "5",
pages = "83--98.e10",
journal = "Cellular and Molecular Gastroenterology and Hepatology",
issn = "2352-345X",
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number = "1",

}

van Koppen, A, Verschuren, L, van den Hoek, AM, Verheij, J, Morrison, MC, Li, K, Nagabukuro, H, Costessi, A, Caspers, MPM, van den Broek, TJ, Sagartz, J, Kluft, C, Beysen, C, Emson, C, van Gool, AJ, Goldschmeding, R, Stoop, R, Bobeldijk-Pastorova, I, Turner, SM, Hanauer, G & Hanemaaijer, R 2018, 'Uncovering a Predictive Molecular Signature for the Onset of NASH-Related Fibrosis in a Translational NASH Mouse Model' Cellular and Molecular Gastroenterology and Hepatology, vol. 5, no. 1, pp. 83-98.e10. https://doi.org/10.1016/j.jcmgh.2017.10.001

Uncovering a Predictive Molecular Signature for the Onset of NASH-Related Fibrosis in a Translational NASH Mouse Model. / van Koppen, Arianne; Verschuren, Lars; van den Hoek, Anita M.; Verheij, Joanne; Morrison, Martine C.; Li, Kelvin; Nagabukuro, Hiroshi; Costessi, Adalberto; Caspers, Martien P. M.; van den Broek, Tim J.; Sagartz, John; Kluft, Cornelis; Beysen, Carine; Emson, Claire; van Gool, Alain J.; Goldschmeding, Roel; Stoop, Reinout; Bobeldijk-Pastorova, Ivana; Turner, Scott M.; Hanauer, Guido; Hanemaaijer, Roeland.

In: Cellular and Molecular Gastroenterology and Hepatology, Vol. 5, No. 1, 2018, p. 83-98.e10.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Uncovering a Predictive Molecular Signature for the Onset of NASH-Related Fibrosis in a Translational NASH Mouse Model

AU - van Koppen, Arianne

AU - Verschuren, Lars

AU - van den Hoek, Anita M.

AU - Verheij, Joanne

AU - Morrison, Martine C.

AU - Li, Kelvin

AU - Nagabukuro, Hiroshi

AU - Costessi, Adalberto

AU - Caspers, Martien P. M.

AU - van den Broek, Tim J.

AU - Sagartz, John

AU - Kluft, Cornelis

AU - Beysen, Carine

AU - Emson, Claire

AU - van Gool, Alain J.

AU - Goldschmeding, Roel

AU - Stoop, Reinout

AU - Bobeldijk-Pastorova, Ivana

AU - Turner, Scott M.

AU - Hanauer, Guido

AU - Hanemaaijer, Roeland

PY - 2018

Y1 - 2018

N2 - Background & Aims The incidence of nonalcoholic steatohepatitis (NASH) is increasing. The pathophysiological mechanisms of NASH and the sequence of events leading to hepatic fibrosis are incompletely understood. The aim of this study was to gain insight into the dynamics of key molecular processes involved in NASH and to rank early markers for hepatic fibrosis. Methods A time-course study in low-density lipoprotein–receptor knockout. Leiden mice on a high-fat diet was performed to identify the temporal dynamics of key processes contributing to NASH and fibrosis. An integrative systems biology approach was used to elucidate candidate markers linked to the active fibrosis process by combining transcriptomics, dynamic proteomics, and histopathology. The translational value of these findings were confirmed using human NASH data sets. Results High-fat-diet feeding resulted in obesity, hyperlipidemia, insulin resistance, and NASH with fibrosis in a time-dependent manner. Temporal dynamics of key molecular processes involved in the development of NASH were identified, including lipid metabolism, inflammation, oxidative stress, and fibrosis. A data-integrative approach enabled identification of the active fibrotic process preceding histopathologic detection using a novel molecular fibrosis signature. Human studies were used to identify overlap of genes and processes and to perform a network biology-based prioritization to rank top candidate markers representing the early manifestation of fibrosis. Conclusions An early predictive molecular signature was identified that marked the active profibrotic process before histopathologic fibrosis becomes manifest. Early detection of the onset of NASH and fibrosis enables identification of novel blood-based biomarkers to stratify patients at risk, development of new therapeutics, and help shorten (pre)clinical experimental time frames.

AB - Background & Aims The incidence of nonalcoholic steatohepatitis (NASH) is increasing. The pathophysiological mechanisms of NASH and the sequence of events leading to hepatic fibrosis are incompletely understood. The aim of this study was to gain insight into the dynamics of key molecular processes involved in NASH and to rank early markers for hepatic fibrosis. Methods A time-course study in low-density lipoprotein–receptor knockout. Leiden mice on a high-fat diet was performed to identify the temporal dynamics of key processes contributing to NASH and fibrosis. An integrative systems biology approach was used to elucidate candidate markers linked to the active fibrosis process by combining transcriptomics, dynamic proteomics, and histopathology. The translational value of these findings were confirmed using human NASH data sets. Results High-fat-diet feeding resulted in obesity, hyperlipidemia, insulin resistance, and NASH with fibrosis in a time-dependent manner. Temporal dynamics of key molecular processes involved in the development of NASH were identified, including lipid metabolism, inflammation, oxidative stress, and fibrosis. A data-integrative approach enabled identification of the active fibrotic process preceding histopathologic detection using a novel molecular fibrosis signature. Human studies were used to identify overlap of genes and processes and to perform a network biology-based prioritization to rank top candidate markers representing the early manifestation of fibrosis. Conclusions An early predictive molecular signature was identified that marked the active profibrotic process before histopathologic fibrosis becomes manifest. Early detection of the onset of NASH and fibrosis enables identification of novel blood-based biomarkers to stratify patients at risk, development of new therapeutics, and help shorten (pre)clinical experimental time frames.

UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85035027016&origin=inward

UR - https://www.ncbi.nlm.nih.gov/pubmed/29276754

U2 - 10.1016/j.jcmgh.2017.10.001

DO - 10.1016/j.jcmgh.2017.10.001

M3 - Article

VL - 5

SP - 83-98.e10

JO - Cellular and Molecular Gastroenterology and Hepatology

JF - Cellular and Molecular Gastroenterology and Hepatology

SN - 2352-345X

IS - 1

ER -