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

Abstract

Background & AimsThe 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.MethodsA 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.ResultsHigh-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.ConclusionsAn 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.

Obeticholic Acid Modulates Serum Metabolites and Gene Signatures Characteristic of Human NASH and Attenuates Inflammation and Fibrosis Progression in Ldlr‐/‐.Leiden Mice

“…However, little is known about the effects of OCA at the molecular pathophysiological level, and a detailed investigation of the anti‐inflammatory and anti‐fibrotic effects of OCA has not been performed to date. Here, we investigated the effects of OCA on hepatic inflammatory and profibrotic processes in the HFD‐fed Ldlr‐/‐.Leiden mouse, which recapitulates many phenotypical and molecular facets of NASH in humans . Previously available data on the effects of OCA are based largely on preclinical studies using experimental conditions that appear less relevant to the clinical situation, such as the use of toxic chemicals to induce liver injury or the use of extreme diets (lacking essential amino acids or containing supra‐physiological concentrations of saturated fat, fructose, or cholesterol).…”

“…Herein we describe a preclinical model of NASH in obesity, Ldlr‐/‐.Leiden mice that develop pronounced liver fibrosis in response to energy‐dense high‐fat diets (HFDs) with a macronutrient composition resembling that of human diets (not requiring amino‐acid deficiency or cholesterol supplementation). The model displays phenotypical and metabolic features of high‐risk patients, including insulin resistance . Combined transcriptomics (liver) and metabolomics (serum) profiling revealed that Ldlr‐/‐.Leiden mice recapitulate many of the molecular pathways of human disease including specific fingerprint genes identified in patients with progressive NASH, as well as lipidome/metabolome signatures of NASH patients.…”

“Single-nucleus RNA-seq2 reveals a functional crosstalk between liver zonation and ploidy”

“…In particular, dysregulation of Akr1d1 has been associated with human NAFLD [66], and upregulation of Wwtr1 (also known as TAZ) in human and murine NASH liver [68]. Furthermore, Tead1 has been proposed as a marker of NASH in murine mouse models [69]. Additionally, Vegfa, Lifr, and Nrp1 have been associated with the intrahepatic ligand-receptor signalling network involved in the pathogenesis of NASH [67] ( Fig.…”

Integrative analysis of blood and gut microbiota data suggests a non-alcoholic fatty liver disease (NAFLD)-related disorder in French SLAdd minipigs

“…In all these three cases, the percentage of pathways putatively related to the NAFLD spectrum was estimated by performing a comparison with a pathway consensus list obtained using 19 papers describing transcriptional profiling 6,8,[14][15][16]49,50,[60][61][62][63][64][65][66][67][68][69] or data meta-analysis 7,51 . A further review paper was also added 27 .…”