Journal
AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY
Volume 290, Issue 6, Pages G1339-G1346Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpgi.00509.2005
Keywords
nonalcoholic fatty liver disease; lysosomes; Bax; Bcl-2 family; cathepsin B
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Funding
- NIDDK NIH HHS [DK-41876, R37 DK041876, R01 DK076852-01, R01 DK076852, R01 DK041876] Funding Source: Medline
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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 Bc1-2 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 Bc1-X-L, a Bax antagonist. Moreover, forced Bc1-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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