Bax inhibition protects against free fatty acid-induced lysosomal permeabilization

Ariel E. Feldstein, Nathan W. Werneburg, Zhengzheng Li, Steven F. Bronk, Gregory James Gores

Research output: Contribution to journalArticle

131 Citations (Scopus)

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 languageEnglish (US)
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume290
Issue number6
DOIs
StatePublished - Jun 2006

Fingerprint

Nonesterified Fatty Acids
Palmitates
Ceramides
Caspases
Lysosomes
Small Interfering RNA
Hepatocytes
Cell Death
Pharmacology
Apoptosis
Liver
Inhibition (Psychology)

Keywords

  • Bax
  • Bcl-2 family
  • Cathepsin B
  • Lysosomes
  • Nonalcoholic fatty liver disease

ASJC Scopus subject areas

  • Gastroenterology
  • Physiology

Cite this

Bax inhibition protects against free fatty acid-induced lysosomal permeabilization. / Feldstein, Ariel E.; Werneburg, Nathan W.; Li, Zhengzheng; Bronk, Steven F.; Gores, Gregory James.

In: American Journal of Physiology - Gastrointestinal and Liver Physiology, Vol. 290, No. 6, 06.2006.

Research output: Contribution to journalArticle

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T1 - Bax inhibition protects against free fatty acid-induced lysosomal permeabilization

AU - Feldstein, Ariel E.

AU - Werneburg, Nathan W.

AU - Li, Zhengzheng

AU - Bronk, Steven F.

AU - Gores, Gregory James

PY - 2006/6

Y1 - 2006/6

N2 - 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.

AB - 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.

KW - Bax

KW - Bcl-2 family

KW - Cathepsin B

KW - Lysosomes

KW - Nonalcoholic fatty liver disease

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