title: The effect of FFAR1 on pioglitazone-mediated attenuation of palmitic acid-induced oxidative stress and apoptosis in βTC6 cells.
abstract: OBJECTIVE
  We sought to determine whether free fatty acid receptor 1 (FFAR1), a receptor for free fatty acids on the β-cell membrane, can mediate the pioglitazone (PIO)-attenuating effect on lipoapoptosis in β cells and its relationship to oxidative stress.
  
  
  METHODS
  The glucose-sensitive mouse beta pancreatic cell line βTC6 was used to investigate the effect of FFAR1 on PIO-attenuating palmitic acid (PA)-induced oxidative stress and apoptosis.
  
  
  RESULTS
  (1) PIO reduced PA-induced lipoapoptosis in β cells and upregulated the expression of FFAR1 at the mRNA and protein levels in a dose- and time-dependent manner. Silencing of FFAR1 expression was shown to weaken the protective effect of PIO on PA-induced lipoapoptosis in βTC6 cells; while lentiviral-mediated overexpression of FFAR1 was shown to enhance the protective effect of PIO against lipoapoptosis in β cells. (2) Downregulation of FFAR1 expression reduced the attenuating effect of PIO on the expression of NAPDH oxidase subunit p47(phox), Bax, cleaved caspase 3, and the production of reactive oxygen specific (ROS) induced by lipotoxicity, thereby preventing the upregulation of the expression of bcl-2. Inducing the overexpression of FFAR1 enhanced the anti-oxidative stress effect of PIO. Similarly, these effects of FFAR1 on PIO were reproduced under conditions of oxidative stress and apoptosis in βTC6 cells that were induced by H2O2. (3) PIO was found to increase the expression of PLCγ, ERK1/2, and PPARγ in lipotoxic β cells. Silencing FFAR1 expression reduced the PIO-mediated increases in the expression of above proteins; while inducing FFAR1 overexpression showed the opposite effect. Use of an inhibitor of PLCγ, ERK1/2, PPARγ was shown to restrict the protective effect of PIO on oxidative stress and lipoapoptosis of β cells.
  
  
  CONCLUSIONS
  FFAR1 can mediate PIO suppression of β-cell lipoapoptosis through anti-oxidative stress, which may be related to the activation of the PLCγ-ERK1/2-PPARγ pathway.
authors.affiliation: Endocrinology Department, the First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, Fujian, China; Department of Endocrinology, The First Clinical Medical College of Fujian Medical University, Fuzhou, Fujian 350005, China.
authors.forename: Ximei
authors.initials: X
authors.lastname: Shen
authors.affiliation: Endocrinology Department, the First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, Fujian, China. Electronic address: liyongy@yahoo.com.
authors.forename: Liyong
authors.initials: L
authors.lastname: Yang
authors.affiliation: Endocrinology Department, the First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, Fujian, China.
authors.forename: Sunjie
authors.initials: S
authors.lastname: Yan
authors.affiliation: Endocrinology Department, the First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, Fujian, China.
authors.forename: Wenfeng
authors.initials: W
authors.lastname: Wei
authors.affiliation: Endocrinology Department, the First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, Fujian, China.
authors.forename: Liyu
authors.initials: L
authors.lastname: Liang
authors.affiliation: Endocrinology Department, the First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, Fujian, China.
authors.forename: Huanhuan
authors.initials: H
authors.lastname: Zheng
authors.affiliation: Endocrinology Department, the First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, Fujian, China.
authors.forename: Xiuhui
authors.initials: X
authors.lastname: Cai
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D002460:Cell Line; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D005230:Fatty Acids, Nonesterified / Q000235:genetics / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000494:pharmacology; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects* / Q000235:genetics; D019308:Palmitic Acid / Q000494:pharmacology*; D000077205:Pioglitazone; D043562:Receptors, G-Protein-Coupled / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D045162:Thiazolidinediones / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
chemical_list: D005230:Fatty Acids, Nonesterified; C473036:Ffar1 protein, mouse; D043562:Receptors, G-Protein-Coupled; D045162:Thiazolidinediones; D019308:Palmitic Acid; D006861:Hydrogen Peroxide; D000077205:Pioglitazone
keywords: Free fatty acid receptor 1; Lipoapoptosis; Oxidative stress; Pioglitazone; β cell