title: Locked nucleic acid antisense inhibitor targeting apolipoprotein C-III efficiently and preferentially removes triglyceride from large very low-density lipoprotein particles in murine plasma.
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.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan; Department of Molecular Innovation in Lipidology, National Cerebral and Cardiovascular Center Research Institute, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan. Electronic address: t-yam@phs.osaka-u.ac.jp.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Yamamoto
authors.affiliation: Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan. Electronic address: obika@phs.osaka-u.ac.jp.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Obika
authors.affiliation: Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan; Department of Molecular Innovation in Lipidology, National Cerebral and Cardiovascular Center Research Institute, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan. Electronic address: moeka6287@gmail.com.
authors.forename: Moeka
authors.initials: M
authors.lastname: Nakatani
authors.affiliation: Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan; Department of Molecular Innovation in Lipidology, National Cerebral and Cardiovascular Center Research Institute, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan. Electronic address: yasuhara-h@phs.osaka-u.ac.jp.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Yasuhara
authors.affiliation: Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan; Department of Molecular Innovation in Lipidology, National Cerebral and Cardiovascular Center Research Institute, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan. Electronic address: wada.fumito.ri@ncvc.go.jp.
authors.forename: Fumito
authors.initials: F
authors.lastname: Wada
authors.affiliation: Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan; Department of Molecular Innovation in Lipidology, National Cerebral and Cardiovascular Center Research Institute, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan; Graduate School of Health Sciences, Osaka Health Science University, Osaka, Japan. Electronic address: belleiko@ncvc.go.jp.
authors.forename: Eiko
authors.initials: E
authors.lastname: Shibata
authors.affiliation: Graduate School of Health Sciences, Osaka Health Science University, Osaka, Japan. Electronic address: masaaki.shibata@ohsu.ac.jp.
authors.forename: Masa-Aki
authors.initials: MA
authors.lastname: Shibata
authors.affiliation: Department of Molecular Innovation in Lipidology, National Cerebral and Cardiovascular Center Research Institute, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan. Electronic address: mshiba@ncvc.go.jp.
authors.forename: Mariko
authors.initials: M
authors.lastname: Harada-Shiba
mesh_terms: D000818:Animals; D053305:Apolipoprotein C-III / Q000097:blood / Q000235:genetics*; D002784:Cholesterol / Q000097:blood; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D008074:Lipoproteins / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009841:Oligonucleotides / Q000494:pharmacology*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D014280:Triglycerides / Q000097:blood*
chemical_list: D053305:Apolipoprotein C-III; D008074:Lipoproteins; D009841:Oligonucleotides; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D014280:Triglycerides; C477371:locked nucleic acid; D002784:Cholesterol
keywords: Antisense oligonucleotide; Apolipoprotein C-III; Bridged nucleic acids; Hyperlipidemia; Locked nucleic acids; Synthetic nucleic acid