Bax inhibition protects against free fatty acid-induced lysosomal permeabilization
Open accessAbstract
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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In other experimental settings, lysosomes are permeabilized before mitochondria via a mechanism that optionally involves BAX recruitment to the lysosomal membrane followed by activation of its pore-forming activity.
“In other experimental settings, however, lysosomes are permeabilized before mitochondria [752, 760, 761], via a mechanism that optionally involves BAX recruitment to the lysosomal membrane followed by the activation of its pore-forming activity [762–765].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [762]
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- Authors
- Feldstein, A. E., Werneburg, N. W., Li, Z., Bronk, S. F., & Gores, G. J.
- Affiliations
- Mayo Clinic (US)
- Cleveland Clinic (US)
- Venue
- American Journal of Physiology-Gastrointestinal and Liver Physiology
- Publisher
- American Physiological Society
- Published
- 2006-06
- Volume
- 290
- Issue
- 6
- Pages
- G1339-G1346
- ISSN
- 0193-1857 (ISSN-L)
- 1522-1547
- PMC
- PMC3056273
- OpenAlex
- W2118912353
- Cited by
- 174
- References
- 43
- Citations by year
- 2026: 4 · 2025: 2 · 2024: 6 · 2023: 5 · 2022: 7 · 2021: 7 · 2020: 2 · 2019: 7 · 2018: 9 · 2017: 8 · 2016: 9 · 2015: 10 · 2014: 9 · 2013: 9 · 2012: 9
- FWCI
- 5.97
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- American Journal of Physiology-Gastrointestinal and Liver Physiology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK076852, DK-41876, R37DK041876, R01DK041876)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
- Keywords
- Bax, lysosomal membrane permeabilization, free fatty acids, palmitate, Bcl-xL, Bcl-2 family proteins, apoptosis, ceramide, caspase-independent cell death, hepatocytes
- MeSH terms
- Animals, Cell Membrane Permeability, Cells, Cultured, Fatty Acids, Nonesterified, Lysosomes, Male, Mice, Inbred C57BL, Palmitic Acid, Hepatocytes, bcl-2-Associated X Protein, Mice
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