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

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

van Koppen, A.
Verschuren, L.
van den Hoek, A.M.
Verheij, J.
Morrison, M.C.
Li, K.
Nagabukuro, H.
Costessi, A.
Caspers, M.P.M.
van den Broek, T.J.
Sagartz, J.
Kluft, C.
Beysen, C.
Emson, C.
van Gool, A.J.
Goldschmeding, R.
Stoop, R.
Bobeldijk-Pastorova, I.
Turner, S.M.
Hanauer, G.
Hanemaaijer, R.

2017

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.

ELSS - Earth, Life and Social Sciences
Life
Healthy Living
Biomedical Innovation
ALT, alanine aminotransferase
AST, aspartate aminotransferase
DEG, differentially expressed genes; Diagnosis
ECM, extracellular matrix
HFD, high-fat diet
IPA, Ingenuity Pathway Analysis
LDLr-/-, low-density lipoprotein receptor knock out
Liver Disease; Metabolic Syndrome
NAFLD, nonalcoholic fatty liver disease
NASH, nonalcoholic steatohepatitis
Systems Biology
THBS1, thrombospontin-1
MHR - Metabolic Health Research MSB - Microbiology and Systems Biology

http://resolver.tudelft.nl/uuid:4df15db4-5938-489e-b10e-dbb24dc9e692

https://doi.org/10.1016/j.jcmgh.2017.10.001

782683

Cellular and Molecular Gastroenterology and Hepatology, 5 (5), 83-98

article