Thematic review series: Lipotoxicity: Many roads to cell dysfunction and cell death lipotoxic lethal and sublethal stress signaling in hepatocytes: Relevance to NASH pathogenesis

Petra Hirsova, Samar H. Ibrabim, Gregory J. Gores, Harmeet Malhi

Research output: Contribution to journalReview articlepeer-review

69 Scopus citations

Abstract

The accumulation of lipids is a histologic and biochemical hallmark of obesity-associated nonalcoholic fatty liver disease (NAFLD). A subset of NALFD patients develops progressive liver disease, termed nonalcoholic steatohepatitis, which is characterized by hepatocellular apoptosis and innate immune system-mediated inflammation. These responses are orchestrated by signaling pathways that can be activated by lipids, directly or indirectly. In this review, we discuss palmitate- and lysophosphatidylcholine (LPC)-induced upregulation of p53-upregulated modulator of apoptosis and cell-surface expression of the death receptor TNF-related apoptosis-inducing ligand receptor 2. Next, we review the activation of stress-induced kinases, mixed lineage kinase 3, and c-Jun N-terminal kinase, and the activation of endoplasmic reticulum stress response and its downstream proapoptotic effector, CAAT/enhancer binding homologous protein, by palmitate and LPC. Moreover, the activation of these stress signaling pathways is linked to the release of proinflammatory, proangiogenic, and profibrotic extracellular vesicles by stressed hepatocytes. This review discusses the signaling pathways induced by lethal and sublethal lipid overload that contribute to the pathogenesis of NAFLD.

Original languageEnglish (US)
Pages (from-to)1758-1770
Number of pages13
JournalJournal of Lipid Research
Volume57
Issue number10
DOIs
StatePublished - Oct 2016

Keywords

  • Apoptosis
  • Cell death
  • Cell signaling
  • Exosomes
  • Extracellular vesicles
  • Fatty acids
  • Lipotoxicity
  • Lysophosphatidylcholine
  • Nonalcoholic fatty liver disease
  • Nonalcoholic steatohepatitis
  • Steatohepatitis

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Cell Biology

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