A novel anti-inflammatory role of GPR120 in intestinal epithelial cells

Abstract

GPR120 (free fatty acid receptor-4) is a G protein-coupled receptor for medium- and long-chain unsaturated fatty acids, including ω-3 fatty acids. Recent studies have shown GPR120 to play cardinal roles in metabolic disorders via modulation of gut hormone secretion and insulin sensitivity and to exert anti-inflammatory effects in macrophages and adipose tissues. However, information on anti-inflammatory role of GPR120 at the level of intestinal epithelium is very limited. Current studies demonstrated differential levels of GPR120 mRNA and protein along the length of the human, mouse, and rat intestine and delineated distinct anti-inflammatory responses following GPR120 activation in model human intestinal epithelial Caco-2 cells, but not in model mouse intestinal epithelial endocrine cell line STC-1. In Caco-2 cells, GPR120 was internalized, bound to β-arrestin-2, and attenuated NF-κB activation in response to 30-min exposure to the agonists GW9508, TUG-891, or docosahexaenoic acid. These effects were abrogated in response to small interfering RNA silencing of β-arrestin-2. Treatment of STC-1 cells with these agonists did not induce receptor internalization and had no effects on NF-κB activation, although treatment with the agonists GW9508 or TUG-891 for 6 h augmented the synthesis and secretion of the gut hormone glucagon-like peptide-1 in this cell line. Our studies for the first time demonstrated a GPR120-mediated novel anti-inflammatory pathway in specific intestinal epithelial cell types that could be of therapeutic relevance to intestinal inflammatory disorders.

FFAR4 (GPR120) Signaling Is Not Required for Anti-Inflammatory and Insulin-Sensitizing Effects of Omega-3 Fatty Acids

“…In this regard, the discovery that FFAR4 seemed to be the main receptor mediating the anti-inflammatory and insulin-sensitizing effects of ω 3-polyunsaturated fatty acids ( ω 3-PUFAs) in adipocytes and macrophages spurred considerable interest in this receptor [17]. In recent years, the anti-inflammatory potential of FFAR4 signaling in other cell types and tissues, that is, Kupffer cells [18], colonic Caco-2 cells [19], and hypothalamus [20], has been investigated.…”

Identification of a Conserved, Orphan G Protein-Coupled Receptor Required for Efficient Pathogen Clearance in Caenorhabditis elegans

“…Although further experiments are required to identify a biological ligand for PCDR-1, immunomodulatory functions for FFAR4, hypocretin, dopamine, and melatonin receptors have been reported in mammals. FFAR4 has an anti-inflammatory role (29), while hypocretin, dopamine, and melatonin receptors are expressed on cells associated with immune function (30)(31)(32) and have been reported to regulate phagocytosis in macrophages (33,34). Therefore, it is possible that the function of PCDR-1 in host defense is conserved, and further studies into its function in C. elegans may provide basic insights into evolutionarily conserved roles of GPCRs in protecting animals from infection.…”

The GPR120 Agonist TUG-891 Inhibits the Motility and Phagocytosis of Mouse Alveolar Macrophages

“…The movement of the cells was analyzed by ImageJ software, and the motility of macrophages was represented by the changes in the cell area and the variation of the cell area, which were used for statistical analysis. The concentration of TUG-891 used in this study was referred to the previous reports [26,28,29]. The concentrations of inhibitors used in this study were also referred to the reports [30][31][32].…”