title: Polyunsaturated Branched-Chain Fatty Acid Geranylgeranoic Acid Induces Unfolded Protein Response in Human Hepatoma Cells.
abstract: The acyclic diterpenoid acid geranylgeranoic acid (GGA) has been reported to induce autophagic cell death in several human hepatoma-derived cell lines; however, the molecular mechanism for this remains unknown. In the present study, several diterpenoids were examined for ability to induce XBP1 splicing and/or lipotoxicity for human hepatoma cell lines. Here we show that three groups of diterpenoids emerged: 1) GGA, 2,3-dihydro GGA and 9-cis retinoic acid induce cell death and XBP1 splicing; 2) all-trans retinoic acid induces XBP1 splicing but little cell death; and 3) phytanic acid, phytenic acid and geranylgeraniol induce neither cell death nor XBP1 splicing. GGA-induced ER stress/ unfolded protein response (UPR) and its lipotoxicity were both blocked by co-treatment with oleic acid. The blocking activity of oleic acid for GGA-induced XBP1 splicing was not attenuated by methylation of oleic acid. These findings strongly suggest that GGA at micromolar concentrations induces the so-called lipid-induced ER stress response/UPR, which is oleate-suppressive, and shows its lipotoxicity in human hepatoma cells.
authors.affiliation: Molecular and Cellular Biology, Graduate School of Human Health Science, University of Nagasaki, Nagasaki, Japan.
authors.forename: Chieko
authors.initials: C
authors.lastname: Iwao
authors.affiliation: Molecular and Cellular Biology, Graduate School of Human Health Science, University of Nagasaki, Nagasaki, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Shidoji
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004224:Diterpenes / Q000737:chemistry / Q000494:pharmacology*; D005231:Fatty Acids, Unsaturated / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D008113:Liver Neoplasms / Q000473:pathology*; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D019301:Oleic Acid / Q000494:pharmacology; D010168:Palmitates / Q000494:pharmacology; D012326:RNA Splicing / Q000187:drug effects / Q000235:genetics; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D056811:Unfolded Protein Response / Q000187:drug effects*; D000071717:X-Box Binding Protein 1
chemical_list: D004268:DNA-Binding Proteins; D004224:Diterpenes; D005231:Fatty Acids, Unsaturated; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; D010168:Palmitates; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; D019301:Oleic Acid; C040155:geranylgeranic acid