title: Free fatty acids inhibit serum deprivation-induced apoptosis through GPR120 in a murine enteroendocrine cell line STC-1.
abstract: Free fatty acids (FFAs) provide an important energy source and also act as signaling molecules. FFAs are known to exert a variety of physiological responses via their G protein-coupled receptors (GPCRs), such as the GPR40 family. Recently, we identified a novel FFA receptor, GPR120, that promotes secretion of glucagon-like peptide-1 (Hirasawa, A., Tsumaya, K., Awaji, T., Katsuma, S., Adachi, T., Yamada, M., Sugimoto, Y., Miyazaki, S., and Tsujimoto, G. (2005) Nat. Med. 11, 90-94). Here we showed that FFAs inhibit serum deprivation-induced apoptosis of murine enteroendocrine STC-1 cells, which express two types of GPCRs, GPR120 and GPR40, for unsaturated long chain FFA. We first found that linolenic acid potently activated ERK and Akt/protein kinase B (Akt) in STC-1 cells. ERK kinase inhibitors significantly reduced the anti-apoptotic effects of linolenic acid. Inhibitors for phosphatidylinositol 3-kinase (PI3K), a major target of which is Akt, significantly reduced the anti-apoptotic effects. Transfection of STC-1 cells with the dominant-negative form of Akt also inhibited the anti-apoptotic effect. These results suggested that the activation of ERK and PI3K-Akt pathways is required for FFA-induced anti-apoptotic effects on STC-1 cells. Transient transfection of STC-1 cells with GPR120 cDNA, but not GPR40 cDNA, enhanced inhibition of caspase-3 activation. RNA interference experiments showed that reduced expression of GPR120, but not GPR40, resulted in reduced ERK activation and reduced effects of FFAs on caspase-3 inhibition. Collectively, these results demonstrated that FFAs promote the activation of ERK and PI3K-Akt pathways mainly via GPR120, leading to the anti-apoptotic effect of STC-1 cells.
authors.affiliation: Bioinformatics Center, Institute for Chemical Research, Kyoto University, Uji, Japan.
authors.forename: Susumu
authors.initials: S
authors.lastname: Katsuma
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Hatae
authors.forename: Takeaki
authors.initials: T
authors.lastname: Yano
authors.forename: Yoshinao
authors.initials: Y
authors.lastname: Ruike
authors.forename: Mai
authors.initials: M
authors.lastname: Kimura
authors.forename: Akira
authors.initials: A
authors.lastname: Hirasawa
authors.forename: Gozoh
authors.initials: G
authors.lastname: Tsujimoto
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001483:Base Sequence; D053148:Caspase 3; D061945:Caspase Inhibitors; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D016895:Culture Media, Serum-Free; D018076:DNA, Complementary / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005230:Fatty Acids, Nonesterified / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D034622:RNA Interference; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D017962:alpha-Linolenic Acid / Q000494:pharmacology
chemical_list: D061945:Caspase Inhibitors; D016895:Culture Media, Serum-Free; D018076:DNA, Complementary; D004791:Enzyme Inhibitors; C498007:FFAR4 protein, mouse; D005230:Fatty Acids, Nonesterified; C473036:Ffar1 protein, mouse; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D043562:Receptors, G-Protein-Coupled; D017962:alpha-Linolenic Acid; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; C505409:Casp3 protein, mouse; D053148:Caspase 3