title: Molecular mechanism investigation of phenobarbital-induced serum cholesterol elevation in rat livers by microarray analysis.
abstract: Phenobarbital (PB) increases serum total cholesterol levels in rodents and humans. To investigate the underlying molecular mechanisms, we performed a microarray analysis on liver of rats treated repeatedly with 100 mg/kg PB, and examined the serum blood chemistry. The serum concentration of non-esterified fatty acids was decreased from day 1 to day 14 except for day 7, and that of cholesterol was increased from day 4 to day 14. The serum concentration of total ketone bodies was increased on day 7, and that of triglycerides was decreased on day 14. Transcript content of glycolytic genes was decreased by PB treatments, while that of lipoprotein lipase was continuously increased, suggesting a notion that repetitive PB treatments impaired glycolysis and stimulated lipolysis in the liver. The hypothesis was examined by using a previously reported flux-balance model. The increase in mRNA content of malic enzyme after the PB treatment agreed well with the flux-balance model result, suggesting the validity of our hypothesis. The findings also suggested that there was an abundance of acetyl-CoA and shortage of glycolytic products after the repeated PB treatments. Although ketogenesis would normally occur under such cellular conditions, it was only weakly observed after the repeated PB treatments, presumably owing to a decrease in HMG-CoA synthase mRNA content. On the other hand, the mRNA content of several cholesterogenic genes was slightly induced by PB treatments. Thus, serum chemistry and microarray results suggested that repeated PB treatments induced cholesterogenesis in rat livers, which may have contributed to the elevation of the serum total cholesterol concentration.
authors.affiliation: Medicinal Safety Research Labs., Sankyo Co. Ltd., 717 Horikoshi, Fukuroi, 437-0065 Shizuoka, Japan. kiyosawa@fuku.sankyo.co.jp
authors.forename: Naoki
authors.initials: N
authors.lastname: Kiyosawa
authors.forename: Kohji
authors.initials: K
authors.lastname: Tanaka
authors.forename: Jun
authors.initials: J
authors.lastname: Hirao
authors.forename: Kazumi
authors.initials: K
authors.lastname: Ito
authors.forename: Noriyo
authors.initials: N
authors.lastname: Niino
authors.forename: Kyoko
authors.initials: K
authors.lastname: Sakuma
authors.forename: Miyuki
authors.initials: M
authors.lastname: Kanbori
authors.forename: Takashi
authors.initials: T
authors.lastname: Yamoto
authors.forename: Sunao
authors.initials: S
authors.lastname: Manabe
authors.forename: Naochika
authors.initials: N
authors.lastname: Matsunuma
mesh_terms: D000818:Animals; D002784:Cholesterol / Q000097:blood* / Q000235:genetics*; D004734:Energy Metabolism / Q000187:drug effects / Q000235:genetics; D005230:Fatty Acids, Nonesterified / Q000097:blood; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D007657:Ketone Bodies / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D010634:Phenobarbital / Q000494:pharmacology*; D010641:Phenotype; D051381:Rats; D011916:Rats, Inbred F344; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014280:Triglycerides / Q000097:blood
chemical_list: D005230:Fatty Acids, Nonesterified; D006993:Hypnotics and Sedatives; D007657:Ketone Bodies; D014280:Triglycerides; D002784:Cholesterol; D010634:Phenobarbital