title: Fenofibrate induces apoptotic injury in cultured human hepatocytes by inhibiting phosphorylation of Akt.
abstract: Fibric acid derivatives have a potent and effective lipid-lowering action, however, the use of these compounds is sometimes limited due to the occurrence of hepatic injury. In the present study, we characterized cell injury induced by fenofibrate in cultured human hepatocytes. Fenofibrate caused a loss of cell viability and nuclear damage as assessed by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling or by DNA electrophoresis, in which caspase activation is involved. The cell injury was accompanied by the shrinkage and the translocation of phosphatidyl serine from inner membrane to the outer membrane as determined by annexin V stain. The mRNA expression for bcl-2 was reduced by fenofibrate. An immunofluorescent stain with antiserum raised against phosphorylated Akt revealed that fenofibrate inhibited insulin-stimulated phosphorylation of Akt. Like fenofibrate, several compounds that inhibit the phosphorylation of Akt, including wortmannin, SH-6 and a high concentration (100 microM) of SB203580, reduced the viability of cultured human hepatocytes. Both nuclear damage and cell injury induced by fenofibrate were reversed by insulin in a concentration-dependent manner. In contrast, bezafibrate or 8(S)-hydroxyeicosatetraenoic acid had no hepatotoxic action. These findings suggest that fenofibrate causes caspase-dependent apoptosis in human hepatocytes by inhibiting phosphorylation of Akt, in which PPARalpha is not involved.
authors.affiliation: Department of Pharmacy, Kyushu University Hospital, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. toskubota@st.hosp.kyushu-u.ac.jp
authors.forename: T
authors.initials: T
authors.lastname: Kubota
authors.forename: T
authors.initials: T
authors.lastname: Yano
authors.forename: K
authors.initials: K
authors.lastname: Fujisaki
authors.forename: Y
authors.initials: Y
authors.lastname: Itoh
authors.forename: R
authors.initials: R
authors.lastname: Oishi
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D017304:Annexin A5 / Q000494:pharmacology; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival; D004247:DNA / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D011345:Fenofibrate / Q000494:pharmacology*; D022781:Hepatocytes / Q000187:drug effects / Q000473:pathology*; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology; D020287:In Situ Nick-End Labeling; D007328:Insulin / Q000378:metabolism; D008856:Microscopy, Fluorescence; D047493:PPAR alpha / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010718:Phosphatidylserines / Q000737:chemistry; D010766:Phosphorylation; D011419:Propidium / Q000494:pharmacology; D021381:Protein Transport; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D017304:Annexin A5; D004791:Enzyme Inhibitors; D006893:Hydroxyeicosatetraenoic Acids; D000960:Hypolipidemic Agents; D007093:Imidazoles; D007328:Insulin; D047493:PPAR alpha; D010718:Phosphatidylserines; D019253:Proto-Oncogene Proteins c-bcl-2; D011725:Pyridines; D012333:RNA, Messenger; D011419:Propidium; C047628:8-hydroxyeicosatetraenoic acid; D004247:DNA; D019869:Phosphatidylinositol 3-Kinases; D020169:Caspases; C093642:SB 203580; D011345:Fenofibrate; D000077191:Wortmannin