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Transcriptomic profiling of guinea pigs with NASH and advanced fibrosis

ABSTRACT: Non-alcoholic steatohepatitis (NASH) is a serious health challenge affecting millions worldwide, and research advances are restricted by the limited availability of preclinical models recapitulating the complex disease etiology and hepatic histopathology. Uniquely, the diet induced guinea pig model develops NASH with fibrosis resembling human histopathology however, no data is available depicting the guinea pig NASH transcriptome. We provide the first high throughput sequencing results on guinea pig NASH with advanced fibrosis. Transcriptomic profiles in guinea pig NASH clearly separated from controls, and pathways involved in fibrosis, inflammation and lipid metabolism were all highly regulated.

ORGANISM(S): Cavia porcellus

PROVIDER: GSE158168 | GEO | 2021/10/06

REPOSITORIES: GEO

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Project description:SUMMARY: This article presents a predictive molecular signature that marks the early onset of fibrosis in a translational nonalcoholic steatohepatitis mouse model. Overlap of genes and processes with human nonalcoholic steatohepatitis and a list of top candidate biomarkers for early fibrosis are described. 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. Keywords: Systems Biology; Metabolic Syndrome; Liver Disease; Diagnosis.

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Transcriptomic profiling of guinea pigs with NASH and advanced fibrosis

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