Bax Inhibition Protects Against Free Fatty Acid-induced Lysosomal Permeabilization

Overview

Journal Am J Physiol Gastrointest Liver Physiol

Publisher American Physiological Society

Specialties Gastroenterology
Physiology

Date 2006 Feb 18

PMID 16484678

Citations 86

Authors

Ariel E Feldstein

Nathan W Werneburg

Zhengzheng Li

Steven F Bronk

Gregory J Gores

Affiliations

Soon will be listed here.

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.

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