CHOP links endoplasmic reticulum stress to NF-κB activation in the pathogenesis of nonalcoholic steatohepatitis

Jeffrey A. Willy, Sara K. Young, James L. Stevens, Howard Masuoka, Ronald Wek

Research output: Contribution to journalArticle

43 Citations (Scopus)

Abstract

Free fatty acid induction of inflammation and cell death is an important feature of nonalcoholic steatohepatitis (NASH) and has been associated with disruption of the endoplasmic reticulum and activation of the unfolded protein response (UPR). After chronic UPR activation, the transcription factor CHOP (GADD153/DDIT3) triggers cell death; however, the mechanisms linking the UPR or CHOP to hepatoceullular injury and inflammation in the pathogenesis of NASH are not well understood. Using HepG2 and primary human hepatocytes, we found that CHOP induces cell death and inflammatory responses after saturated free fatty acid exposure by activating NF-κB through a pathway involving IRAK2 expression, resulting in secretion of cytokines IL-8 and TNFα directly from hepatocytes. TNFα facilitates hepatocyte death upon exposure to saturated free fatty acids, and secretion of both IL-8 and TNFα contribute to inflammation. Of interest, CHOP/NF-κB signaling is not conserved in primary rodent hepatocytes. Our studies suggest that CHOP plays a vital role in the pathophysiology of NASH by induction of secreted factors that trigger inflammation and hepatocellular death via a signaling pathway specific to human hepatocytes.

Original languageEnglish
Pages (from-to)2190-2204
Number of pages15
JournalMolecular Biology of the Cell
Volume26
Issue number12
DOIs
StatePublished - Jun 15 2015

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Endoplasmic Reticulum Stress
Hepatocytes
Unfolded Protein Response
Nonesterified Fatty Acids
Inflammation
Cell Death
Interleukin-8
Fatty Acids
Transcription Factor CHOP
Endoplasmic Reticulum
Rodentia
Non-alcoholic Fatty Liver Disease
Cytokines
Wounds and Injuries

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

CHOP links endoplasmic reticulum stress to NF-κB activation in the pathogenesis of nonalcoholic steatohepatitis. / Willy, Jeffrey A.; Young, Sara K.; Stevens, James L.; Masuoka, Howard; Wek, Ronald.

In: Molecular Biology of the Cell, Vol. 26, No. 12, 15.06.2015, p. 2190-2204.

Research output: Contribution to journalArticle

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