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Hepatic expression profiling identifies steatosis-independent and steatosis-driven advanced fibrosis genes

Abstract

Chronic liver disease (CLD) is associated with tissue-destructive fibrosis. Considering that common mechanisms drive fibrosis across etiologies, and that steatosis is an important cofactor for pathology, we performed RNA sequencing on liver biopsies of patients with different fibrosis stages, resulting from infection with hepatitis C virus (HCV) (with or without steatosis) or fatty liver disease. In combination with enhanced liver fibrosis score correlation analysis, we reveal a common set of genes associated with advanced fibrosis, as exemplified by those encoding the transcription factor ETS-homologous factor (EHF) and the extracellular matrix protein versican (VCAN). We identified 17 fibrosis-associated genes as candidate EHF targets and demonstrated that EHF regulates multiple fibrosis-associated genes, including VCAN, in hepatic stellate cells. Serum VCAN levels were also elevated in advanced fibrosis patients. Comparing biopsies from patients with HCV with or without steatosis, we identified a steatosis-enriched gene set associated with advanced fibrosis, validating follistatin-like protein 1 (FSTL1) as an exemplar of this profile. In patients with advanced fibrosis, serum FSTL1 levels were elevated in those with steatosis (versus those without). Liver Fstl1 mRNA levels were also elevated in murine CLD models. We thus reveal a common gene signature for CLD-associated liver fibrosis and potential biomarkers and/or targets for steatosis-associated liver fibrosis.

Type Journal
ISBN 2379-3708 (Electronic) 2379-3708 (Linking)
Authors Ramnath, D.; Irvine, K. M.; Lukowski, S. W.; Horsfall, L. U.; Loh, Z.; Clouston, A. D.; Patel, P. J.; Fagan, K. J.; Iyer, A.; Lampe, G.; Stow, J. L.; Schroder, K.; Fairlie, D. P.; Powell, J. E.; Powell, E. E.; Sweet, M. J.
Responsible Garvan Author Dr Joseph Powell
Publisher Name Journal of Clinical Investigation Insight
Published Date 2018-07-25
Published Volume 3
Published Issue 14
Published Pages e120274
Status Always Electronic
DOI 10.1172/jci.insight.120274
URL link to publisher's version https://www.ncbi.nlm.nih.gov/pubmed/30046009
OpenAccess link to author's accepted manuscript version https://publications.gimr.garvan.org.au/open-access/14677