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: Chieko Iwao, Yoshihiro Shidoji
• Journal: PloS one (PLoS One) Vol. 10 Issue 7 Pg. e0132761 ( 2015) ISSN: 1932-6203 [Electronic] United States
• PMID: 26186544 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA-Binding Proteins
• Diterpenes
• Fatty Acids, Unsaturated
• MAP1LC3A protein, human
• Microtubule-Associated Proteins
• Palmitates
• Regulatory Factor X Transcription Factors
• Transcription Factors
• X-Box Binding Protein 1
• XBP1 protein, human
• Oleic Acid
• geranylgeranic acid

Topics

• Carcinoma, Hepatocellular (pathology)
• Cell Death (drug effects)
• Cell Line, Tumor
• Cell Nucleus (drug effects, metabolism)
• DNA-Binding Proteins (genetics, metabolism)
• Diterpenes (chemistry, pharmacology)
• Fatty Acids, Unsaturated (chemistry, pharmacology)
• Humans
• Inhibitory Concentration 50
• Liver Neoplasms (pathology)
• Microtubule-Associated Proteins (metabolism)
• Oleic Acid (pharmacology)
• Palmitates (pharmacology)
• RNA Splicing (drug effects, genetics)
• Regulatory Factor X Transcription Factors
• Transcription Factors (genetics, metabolism)
• Unfolded Protein Response (drug effects)
• X-Box Binding Protein 1