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Am J Physiol Gastrointest Liver Physiol (February 16, 2006). doi:10.1152/ajpgi.00509.2005
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Submitted on October 27, 2005
Accepted on January 24, 2006

Bax Inhibition Protects Against Free Fatty Acid Induced Lysosomal Permeabilization

Ariel E. Feldstein1, Nathan W. Werneburg2, ZhengZheng Li1, Steven F. Bronk2, and Gregory J. Gores2*

1 Department of Pediatric Gastroenterology and Cell Biology, Clevelend Clinic Foundation, Cleveland, OH, USA
2 Mayo Clinic College of Medicine, Rochester, MN, USA

* To whom correspondence should be addressed. E-mail: gores.gregory{at}mayo.edu.

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 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 free fatty acid 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 free fatty acid-mediated lysosomal permeabilization and subsequent cell death.




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