期刊
ENDOCRINOLOGY
卷 148, 期 1, 页码 293-299出版社
ENDOCRINE SOC
DOI: 10.1210/en.2006-0998
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资金
- NIA NIH HHS [AG19602] Funding Source: Medline
- NIEHS NIH HHS [ES03456, ES05865] Funding Source: Medline
- NINDS NIH HHS [NS041208] Funding Source: Medline
- NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES [R01ES003456] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON AGING [R01AG019602] Funding Source: NIH RePORTER
A major characteristic of type 2 diabetes mellitus (T2DM) is insulin resistance in skeletal muscle. A growing body of evidence indicates that oxidative stress that results from increased production of reactive oxygen species and/or reactive nitrogen species leads to insulin resistance, tissue damage, and other complications observed in T2DM. It has been suggested that muscular free fatty acid accumulation might be responsible for the mitochondrial dysfunction and insulin resistance seen in T2DM, although the mechanisms by which increased levels of free fatty acid lead to insulin resistance are not well understood. To help resolve this situation, we report that saturated fatty acid palmitate stimulated the expression of inducible nitric oxide (NO) synthase and the production of reactive oxygen species and NO in L6 myotubes. Additionally, palmitate caused a significant dose-dependent increase in mitochondrial DNA (mtDNA) damage and a subsequent decrease in L6 myotube viability and ATP levels at concentrations as low as 0.5 mM. Furthermore, palmitate induced apoptosis, which was detected by DNA fragmentation, caspase-3 cleavage, and cytochrome c release. N-acetyl cysteine, a precursor compound for glutathione formation, aminoguanidine, an inducible NO synthase inhibitor, and 5,10,15,20-tetrakis(4-sulphonatophenyl) porphyrinato iron (III), a peroxynitrite inhibitor, all prevented palmitate-induced mtDNA damage and diminished palmitate-induced cytotoxicity. We conclude that exposure of L6 myotubes to palmitate induced mtDNA damage and triggered mitochondrial dysfunction, which caused apoptosis. Additionally, our findings indicate that palmitate induced mtDNA damage and cytotoxicity in skeletal muscle cells were caused by overproduction of peroxynitrite.
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