Bax inhibition protects against free fatty acid-induced lysosomal permeabilization

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 e...

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Published inAmerican journal of physiology: Gastrointestinal and liver physiology Vol. 53; no. 6; p. G1339
Main Authors Feldstein, Ariel E, Werneburg, Nathan W, Li, ZhengZheng, Bronk, Steven F, Gores, Gregory J
Format Journal Article
LanguageEnglish
Published Bethesda American Physiological Society 01.06.2006
Subjects
Apoptosis
Cells
Fatty acids
Gene expression
Liver
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Summary: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. [PUBLICATION ABSTRACT]
ISSN:0193-1857
1522-1547