Spatial Molecular and Cellular Determinants of STAT3 Activation in Liver Fibrosis Progression in Non-alcoholic Fatty Liver Disease

Authors

Jingjing Jiao
Jessica I Sanchez
Omar A Saldarriaga
Luisa M Solis
David J Tweardy
Dipen M Maru
Heather L Stevenson
Laura Beretta

Publication Date

2-1-2023

Journal

JHEP Report

Abstract

BACKGROUND & AIMS: The prevalence of non-alcoholic fatty liver disease (NAFLD) and its severe form, non-alcoholic steatohepatitis (NASH), is increasing. Individuals with NASH often develop liver fibrosis and advanced liver fibrosis is the main determinant of mortality in individuals with NASH. We and others have reported that STAT3 contributes to liver fibrosis and hepatocellular carcinoma in mice.

METHODS: Here, we explored whether STAT3 activation in hepatocyte and non-hepatocyte areas, measured by phospho-STAT3 (pSTAT3), is associated with liver fibrosis progression in 133 patients with NAFLD. We further characterized the molecular and cellular determinants of STAT3 activation by integrating spatial distribution and transcriptomic changes in fibrotic NAFLD livers.Results: pSTAT3 scores in non-hepatocyte areas progressively increased with fibrosis severity (r = 0.53,

CONCLUSION: Increased understanding of the spatial dependence of STAT3 signaling in NASH and liver fibrosis progression could lead to novel targeted treatment approaches.

IMPACT AND IMPLICATIONS: Advanced liver fibrosis is the main determinant of mortality in patients with NASH. This study showed using liver biopsies from 133 patients with NAFLD, that STAT3 activation in non-hepatocyte areas is strongly associated with fibrosis severity, inflammation, and progression to NASH. STAT3 activation was enriched in hepatic progenitor cells (HPCs) and sinusoidal endothelial cells (SECs), as determined by innovative technologies interrogating the spatial distribution of pSTAT3. Finally, STAT3 inhibition in mice resulted in reduced liver fibrosis and depletion of HPCs, suggesting that STAT3 activation in HPCs contributes to their expansion and fibrogenesis in NAFLD.

Keywords

fibrosis, STAT3, NAFLD, NASH, cirrhosis, liver cancer

Comments

Supplementary Materials

PMID: 36687470