Transcriptional regulation of Hepatic Stellate Cell activation in NASH

Scientific Reports
Ann-Britt MarcherKim Ravnskjaer

Abstract

Non-alcoholic steatohepatitis (NASH) signified by hepatic steatosis, inflammation, hepatocellular injury, and fibrosis is a growing cause of chronic liver disease, cirrhosis, and hepatocellular carcinoma. Hepatic fibrosis resulting from accumulation of extracellular matrix proteins secreted by hepatic myofibroblasts plays an important role in disease progression. Activated hepatic stellate cells (HSCs) have been identified as the primary source of myofibroblasts in animal models of hepatotoxic liver injury; however, so far HSC activation and plasticity have not been thoroughly investigated in the context of NASH-related fibrogenesis. Here we have determined the time-resolved changes in the HSC transcriptome during development of Western diet- and fructose-induced NASH in mice, a NASH model recapitulating human disease. Intriguingly, HSC transcriptional dynamics are highly similar across disease models pointing to HSC activation as a point of convergence in the development of fibrotic liver disease. Bioinformatic interrogation of the promoter sequences of activated genes combined with loss-of-function experiments indicates that the transcriptional regulators ETS1 and RUNX1 act as drivers of NASH-associated HSC plasticity. Taken ...Continue Reading

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Datasets Mentioned

BETA
GSE78853
GSE101343
73
GSE116987

Methods Mentioned

BETA
FACS
biopsies
density gradient centrifugation
fluorescence-activated cell sorting
transfection

Software Mentioned

R
Homer
Go
EdgeR
Metacore
LSM
Clarivate Analytics
Huygens
TiCoNE
PAMK

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