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Locked nucleic acid antisense inhibitor targeting apolipoprotein C-III efficiently and preferentially removes triglyceride from large very low-density lipoprotein particles in murine plasma.
- Source :
-
European journal of pharmacology [Eur J Pharmacol] 2014 Jan 15; Vol. 723, pp. 353-9. Date of Electronic Publication: 2013 Nov 20. - Publication Year :
- 2014
-
Abstract
- A 20-mer phosphorothioate antisense oligodeoxyribonucleotide having locked nucleic acids (LNA-AON) was used to reduce elevated serum triglyceride levels in mice. We repeatedly administered LNA-AON, which targets murine apolipoprotein C-III mRNA, to high-fat-fed C57Bl/6J male mice for 2 weeks. The LNA-AON showed efficient dose-dependent reductions in hepatic apolipoprotein C-III mRNA and decreased serum apolipoprotein C-III protein concentrations, along with efficient dose-dependent reductions in serum triglyceride concentrations and attenuation of fat accumulation in the liver. Through precise lipoprotein profiling analysis of sera, we found that serum reductions in triglyceride and cholesterol levels were largely a result of decreased serum very low-density lipoprotein (VLDL)-triglycerides and -cholesterol. It is noteworthy that larger VLDL particles were more susceptible to removal from blood than smaller particles, resulting in a shift in particle size distribution to smaller diameters. Histopathologically, fatty changes were markedly reduced in antisense-treated mice, while moderate granular degeneration was frequently seen the highest dose of LNA-AON. The observed granular degeneration of hepatocytes may be associated with moderate elevation in the levels of serum transaminases. In conclusion, we developed an LNA-based selective inhibitor of apolipoprotein C-III. Although it remains necessary to eliminate its potential hepatotoxicity, the present LNA-AON will be helpful for further elucidating the molecular biology of apolipoprotein C-III.<br /> (© 2013 Published by Elsevier B.V.)
- Subjects :
- Animals
Apolipoprotein C-III blood
Cholesterol blood
Kidney drug effects
Kidney pathology
Lipoproteins blood
Liver drug effects
Liver metabolism
Liver pathology
Male
Mice
Mice, Inbred C57BL
RNA, Messenger metabolism
Apolipoprotein C-III genetics
Oligonucleotides pharmacology
Oligonucleotides, Antisense pharmacology
Triglycerides blood
Subjects
Details
- Language :
- English
- ISSN :
- 1879-0712
- Volume :
- 723
- Database :
- MEDLINE
- Journal :
- European journal of pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 24269597
- Full Text :
- https://doi.org/10.1016/j.ejphar.2013.11.004