Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTAZ1226)

• DOT Name: Free fatty acid receptor 4 (FFAR4)
• Synonyms: G-protein coupled receptor 120; G-protein coupled receptor 129; G-protein coupled receptor GT01; G-protein coupled receptor PGR4; Omega-3 fatty acid receptor 1
• Gene Name: FFAR4
• UniProt ID: FFAR4_HUMAN
• PDB ID: 8G59; 8H4I; 8H4K; 8H4L; 8ID3; 8ID4; 8ID6; 8ID8; 8ID9; 8IYS
• Pfam ID: PF00001
• Sequence:
  MSPECARAAGDAPLRSLEQANRTRFPFFSDVKGDHRLVLAAVETTVLVLIFAVSLLGNVC
  ALVLVARRRRRGATACLVLNLFCADLLFISAIPLVLAVRWTEAWLLGPVACHLLFYVMTL
  SGSVTILTLAAVSLERMVCIVHLQRGVRGPGRRARAVLLALIWGYSAVAALPLCVFFRVV
  PQRLPGADQEISICTLIWPTIPGEISWDVSFVTLNFLVPGLVIVISYSKILQITKASRKR
  LTVSLAYSESHQIRVSQQDFRLFRTLFLLMVSFFIMWSPIIITILLILIQNFKQDLVIWP
  SLFFWVVAFTFANSALNPILYNMTLCRNEWKKIFCCFWFPEKGAILTDTSVKRNDLSIIS
  G
• Function: [Isoform 2]: G-protein-coupled receptor for long-chain fatty acids (LCFAs) with a major role in adipogenesis, energy metabolism and inflammation. Signals via G-protein and beta-arrestin pathways. LCFAs sensing initiates activation of phosphoinositidase C-linked G proteins GNAQ and GNA11 (G(q)/G(11)), inducing a variety of cellular responses via second messenger pathways such as intracellular calcium mobilization, modulation of cyclic adenosine monophosphate (cAMP) production, and mitogen-activated protein kinases (MAPKs). After LCFAs binding, associates with beta-arrestin ARRB2 that acts as an adapter protein coupling the receptor to specific downstream signaling pathways, as well as mediating receptor endocytosis. In response to dietary fats, plays an important role in the regulation of adipocyte proliferation and differentiation. Acts as a receptor for omega-3 polyunsaturated fatty acids (PUFAs) at primary cilium of perivascular preadipocytes, initiating an adipogenic program via cAMP and CTCF-dependent chromatin remodeling that ultimately results in transcriptional activation of adipogenic genes and cell cycle entry. Induces differentiation of brown adipocytes probably via autocrine and endocrine functions of FGF21 hormone. Activates brown adipocytes by initiating intracellular calcium signaling that leads to mitochondrial depolarization and fission, and overall increased mitochondrial respiration. Consequently stimulates fatty acid uptake and oxidation in mitochondria together with UCP1-mediated thermogenic respiration, eventually reducing fat mass. Regulates bi-potential differentiation of bone marrow mesenchymal stem cells toward osteoblasts or adipocytes likely by up-regulating distinct integrins. In response to dietary fats regulates hormone secretion and appetite. Stimulates GIP and GLP1 secretion from enteroendocrine cells as well as GCG secretion in pancreatic alpha cells, thereby playing a role in the regulation of blood glucose levels. Negatively regulates glucose-induced SST secretion in pancreatic delta cells. Mediates LCFAs inhibition of GHRL secretion, an appetite-controlling hormone. In taste buds, contributes to sensing of dietary fatty acids by the gustatory system. During the inflammatory response, promotes anti-inflammatory M2 macrophage differentiation in adipose tissue. Mediates the anti-inflammatory effects of omega-3 PUFAs via inhibition of NLRP3 inflammasome activation. In this pathway, interacts with adapter protein ARRB2 and inhibits the priming step triggered by Toll-like receptors (TLRs) at the level of TAK1 and TAB1. Further inhibits the activation step when ARRB2 directly associates with NLRP3, leading to inhibition of pro-inflammatory cytokine release. Mediates LCFAs anti-apoptotic effects; [Isoform 1]: Receptor for LCFAs decoupled from G-protein signaling. May signal through beta-arrestin pathway. After LCFAs binding, associates with beta-arrestin ARRB2 that may act as an adapter protein coupling the receptor to specific downstream signaling pathways, as well as mediating receptor endocytosis.
• Tissue Specificity: .The predominant isoform in human tissues. Expressed in adipose tissue, pancreatic islets, lung and brain. Expressed in alpha cells of pancreatic islets . Expressed in primary cilia of perivascular preadipocytes of white adipose tissue (at protein level) .; Abundant expression in the intestinal tract. Expressed in colonic intraepithelial neuroendocrine cells.
• Reactome Pathway:
  G alpha (q) signalling events (R-HSA-416476)
  Free fatty acid receptors (R-HSA-444209)
  Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) (R-HSA-381771)

Molecular Interaction Atlas (MIA) of This DOT

1 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Free fatty acid receptor 4 (FFAR4).	[1]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Free fatty acid receptor 4 (FFAR4).	[2]

References

• [1] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [2] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.