Transcriptional regulation of Hepatic Stellate Cell activation in NASH

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Resumé

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 together, our results implicate HSC activation and transcriptional plasticity as key aspects of NASH pathophysiology.

OriginalsprogEngelsk
Artikelnummer2324
TidsskriftScientific Reports
Vol/bind9
Udgave nummer1
Antal sider55
ISSN2045-2322
DOI
StatusUdgivet - 20. feb. 2019

Fingeraftryk

Hepatic Stellate Cells
Fatty Liver
Liver
Liver Diseases
Extracellular Matrix Proteins
Wounds and Injuries
Fructose
Computational Biology
Transcriptome
Liver Cirrhosis
Transcriptional Activation
Hepatocellular Carcinoma

Citer dette

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title = "Transcriptional regulation of Hepatic Stellate Cell activation in NASH",
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 together, our results implicate HSC activation and transcriptional plasticity as key aspects of NASH pathophysiology.",
author = "Ann-Britt Marcher and Bendixen, {Sofie M} and Terkelsen, {Mike K} and Hohmann, {Sonja S} and Hansen, {Maria H} and Larsen, {Bj{\o}rk D} and Susanne Mandrup and Henrik Dimke and S{\"o}nke Detlefsen and Kim Ravnskjaer",
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Transcriptional regulation of Hepatic Stellate Cell activation in NASH. / Marcher, Ann-Britt; Bendixen, Sofie M; Terkelsen, Mike K; Hohmann, Sonja S; Hansen, Maria H; Larsen, Bjørk D; Mandrup, Susanne; Dimke, Henrik; Detlefsen, Sönke; Ravnskjaer, Kim.

I: Scientific Reports, Bind 9, Nr. 1, 2324, 20.02.2019.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Transcriptional regulation of Hepatic Stellate Cell activation in NASH

AU - Marcher, Ann-Britt

AU - Bendixen, Sofie M

AU - Terkelsen, Mike K

AU - Hohmann, Sonja S

AU - Hansen, Maria H

AU - Larsen, Bjørk D

AU - Mandrup, Susanne

AU - Dimke, Henrik

AU - Detlefsen, Sönke

AU - Ravnskjaer, Kim

PY - 2019/2/20

Y1 - 2019/2/20

N2 - 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 together, our results implicate HSC activation and transcriptional plasticity as key aspects of NASH pathophysiology.

AB - 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 together, our results implicate HSC activation and transcriptional plasticity as key aspects of NASH pathophysiology.

U2 - 10.1038/s41598-019-39112-6

DO - 10.1038/s41598-019-39112-6

M3 - Journal article

C2 - 30787418

VL - 9

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

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