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 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.
Department of Pediatric Gastroenterology and Cell Biology, Cleveland, USA. gores.gregory@mayo.edu
Ariel E
AE
Feldstein
Nathan W
NW
Werneburg
Zhengzheng
Z
Li
Steven F
SF
Bronk
Gregory J
GJ
Gores
D000818:Animals; D002463:Cell Membrane Permeability / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D005230:Fatty Acids, Nonesterified / Q000494:pharmacology; D022781:Hepatocytes / Q000187:drug effects / Q000502:physiology*; D008247:Lysosomes / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019308:Palmitic Acid / Q000494:pharmacology*; D051028:bcl-2-Associated X Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism*
C494827:Bax protein, mouse; D005230:Fatty Acids, Nonesterified; D051028:bcl-2-Associated X Protein; D019308:Palmitic Acid