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Am J Physiol Gastrointest Liver Physiol. 2006 Jun;290(6):G1339-46. Epub 2006 Feb 16.

Bax inhibition protects against free fatty acid-induced lysosomal permeabilization.

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  • 1Department of Pediatric Gastroenterology and Cell Biology, Cleveland, USA. gores.gregory@mayo.edu

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-X(L), a Bax antagonist. Moreover, forced Bcl-X(L) 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.

PMID:
16484678
[PubMed - indexed for MEDLINE]
PMCID:
PMC3056273
Free PMC Article
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