A hedgehog survival pathway in 'undead' lipotoxic hepatocytes

Keisuke Kakisaka, Sophie C. Cazanave, Nathan W. Werneburg, Nataliya Razumilava, Joachim C. Mertens, Steve F. Bronk, Gregory James Gores

Research output: Contribution to journalArticle

36 Scopus citations

Abstract

Background & Aims: Ballooned hepatocytes in non-alcoholic steatohepatitis (NASH) generate sonic hedgehog (SHH). This observation is consistent with a cellular phenotype in which the cell death program has been initiated but cannot be executed. Our aim was to determine whether ballooned hepatocytes have potentially disabled the cell death execution machinery, and if so, can their functional biology be modeled in vitro. Methods: Immunohistochemistry was performed on human NASH specimens. In vitro studies were performed using HuH-7 cells with shRNA targeted knockdown of caspase 9 (shC9 cells) or primary hepatocytes from caspase 3-/- mice. Results: Ballooned hepatocytes in NASH display diminished expression of caspase 9. This phenotype was modeled using shC9 cells; these cells were resistant to lipoapoptosis by palmitate (PA) or lysophosphatidylcholine (LPC) despite lipid droplet formation. During lipid loading by either PA or LPC, shC9 cells activate JNK which induces SHH expression via AP-1. An autocrine hedgehog survival signaling pathway was further delineated in both shC9 and caspase 3 -/- cells during lipotoxic stress. Conclusions: Ballooned hepatocytes in NASH downregulate caspase 9, a pivotal caspase executing the mitochondrial pathway of apoptosis. Hepatocytes engineered to reduce caspase 9 expression are resistant to lipoapoptosis, in part, due to a hedgehog autocrine survival signaling pathway.

Original languageEnglish (US)
Pages (from-to)844-851
Number of pages8
JournalJournal of Hepatology
Volume57
Issue number4
DOIs
StatePublished - Oct 2012

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Keywords

  • c-Jun-N-terminal kinase (JNK)
  • Caspase 3
  • Lipoapoptosis
  • Lysophosphatidylcholine
  • Palmitate

ASJC Scopus subject areas

  • Hepatology

Cite this

Kakisaka, K., Cazanave, S. C., Werneburg, N. W., Razumilava, N., Mertens, J. C., Bronk, S. F., & Gores, G. J. (2012). A hedgehog survival pathway in 'undead' lipotoxic hepatocytes. Journal of Hepatology, 57(4), 844-851. https://doi.org/10.1016/j.jhep.2012.05.011