Bax inhibition protects against free fatty acid-induced lysosomal permeabilization

Ariel E. Feldstein, Nathan W. Werneburg, Zhengzheng Li, Steven F. Bronk, Gregory J. Gores

Research output: Contribution to journalArticle

134 Scopus citations

Abstract

Lysosomal permeabilization is a key feature of hepatocyte lipotoxicity, yet the mechanisms mediating this critical cellular event are unclear. This study examined the mechanisms involved in free fatty acid (FFA)-induced lysosomal permeabilization and the role of Bax, a Bcl-2 family member, in this event. Exposure of liver cells to palmitate induced Bax activation and translocation to lysosomes. Studies to suppress Bax activation either by pharmacological approaches or small interfering-RNA-mediated inhibition of Bax expression showed that lysosomal permeabilization is Bax dependent. In addition, palmitate treatment resulted in a significant decrease in Bcl-XL, a Bax antagonist. Moreover, forced Bcl-XL expression blocked lysosomal permeabilization. Lysosomal permeabilization by FFA was ceramide and caspase independent. Finally, paradigms that inhibit lysosomal permeabilization also reduced apoptosis. In conclusion, these data strongly support a regulatory role for Bax in FFA-mediated lysosomal permeabilization and subsequent cell death.

Original languageEnglish (US)
Pages (from-to)G1339-G1346
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume290
Issue number6
DOIs
StatePublished - Jun 1 2006

Keywords

  • Bax
  • Bcl-2 family
  • Cathepsin B
  • Lysosomes
  • Nonalcoholic fatty liver disease

ASJC Scopus subject areas

  • Physiology
  • Hepatology
  • Gastroenterology
  • Physiology (medical)

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