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 language | English (US) |
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Pages (from-to) | G1339-G1346 |
Journal | American Journal of Physiology - Gastrointestinal and Liver Physiology |
Volume | 290 |
Issue number | 6 |
DOIs | |
State | Published - Jun 2006 |
Keywords
- Bax
- Bcl-2 family
- Cathepsin B
- Lysosomes
- Nonalcoholic fatty liver disease
ASJC Scopus subject areas
- Physiology
- Hepatology
- Gastroenterology
- Physiology (medical)