Skip to main content

Epithelial splicing regulatory protein 2-mediated alternative splicing reprograms hepatocytes in severe alcoholic hepatitis.

Publication ,  Journal Article
Hyun, J; Sun, Z; Ahmadi, AR; Bangru, S; Chembazhi, UV; Du, K; Chen, T; Tsukamoto, H; Rusyn, I; Kalsotra, A; Diehl, AM
Published in: J Clin Invest
April 1, 2020

Severe alcoholic hepatitis (SAH) is a deadly liver disease without an effective medical therapy. Although SAH mortality is known to correlate with hepatic accumulation of immature liver cells, why this occurs and how it causes death are unclear. Here, we demonstrate that expression of epithelial splicing regulatory protein 2 (ESRP2), an RNA-splicing factor that maintains the nonproliferative, mature phenotype of adult hepatocytes, was suppressed in both human SAH and various mouse models of SAH in parallel with the severity of alcohol consumption and liver damage. Inflammatory cytokines released by excessive alcohol ingestion reprogrammed adult hepatocytes into proliferative, fetal-like cells by suppressing ESRP2. Sustained loss of ESRP2 permitted reemergence of a fetal RNA-splicing program that attenuates the Hippo signaling pathway and thus allows fetal transcriptional regulators to accumulate in adult liver. We further showed that depleting ESRP2 in mice exacerbated alcohol-induced steatohepatitis, enabling surviving hepatocytes to shed adult hepatocyte functions and become more regenerative, but threatening overall survival by populating the liver with functionally immature hepatocytes. Our findings revealed a mechanism that explains why liver failure develops in patients with the clinical syndrome of SAH, suggesting that recovery from SAH might be improved by limiting adult-to-fetal reprogramming in hepatocytes.

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

J Clin Invest

DOI

EISSN

1558-8238

Publication Date

April 1, 2020

Volume

130

Issue

4

Start / End Page

2129 / 2145

Location

United States

Related Subject Headings

  • Signal Transduction
  • Severity of Illness Index
  • RNA-Binding Proteins
  • Mice, Knockout
  • Mice
  • Male
  • Immunology
  • Humans
  • Hepatocytes
  • Hepatitis, Alcoholic
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Hyun, J., Sun, Z., Ahmadi, A. R., Bangru, S., Chembazhi, U. V., Du, K., … Diehl, A. M. (2020). Epithelial splicing regulatory protein 2-mediated alternative splicing reprograms hepatocytes in severe alcoholic hepatitis. J Clin Invest, 130(4), 2129–2145. https://doi.org/10.1172/JCI132691
Hyun, Jeongeun, Zhaoli Sun, Ali Reza Ahmadi, Sushant Bangru, Ullas V. Chembazhi, Kuo Du, Tianyi Chen, et al. “Epithelial splicing regulatory protein 2-mediated alternative splicing reprograms hepatocytes in severe alcoholic hepatitis.J Clin Invest 130, no. 4 (April 1, 2020): 2129–45. https://doi.org/10.1172/JCI132691.
Hyun J, Sun Z, Ahmadi AR, Bangru S, Chembazhi UV, Du K, et al. Epithelial splicing regulatory protein 2-mediated alternative splicing reprograms hepatocytes in severe alcoholic hepatitis. J Clin Invest. 2020 Apr 1;130(4):2129–45.
Hyun, Jeongeun, et al. “Epithelial splicing regulatory protein 2-mediated alternative splicing reprograms hepatocytes in severe alcoholic hepatitis.J Clin Invest, vol. 130, no. 4, Apr. 2020, pp. 2129–45. Pubmed, doi:10.1172/JCI132691.
Hyun J, Sun Z, Ahmadi AR, Bangru S, Chembazhi UV, Du K, Chen T, Tsukamoto H, Rusyn I, Kalsotra A, Diehl AM. Epithelial splicing regulatory protein 2-mediated alternative splicing reprograms hepatocytes in severe alcoholic hepatitis. J Clin Invest. 2020 Apr 1;130(4):2129–2145.

Published In

J Clin Invest

DOI

EISSN

1558-8238

Publication Date

April 1, 2020

Volume

130

Issue

4

Start / End Page

2129 / 2145

Location

United States

Related Subject Headings

  • Signal Transduction
  • Severity of Illness Index
  • RNA-Binding Proteins
  • Mice, Knockout
  • Mice
  • Male
  • Immunology
  • Humans
  • Hepatocytes
  • Hepatitis, Alcoholic