Short-chain free fatty acid receptors FFA2/GPR43 and FFA3/GPR41 as new potential therapeutic targets - PubMed (original) (raw)

Short-chain free fatty acid receptors FFA2/GPR43 and FFA3/GPR41 as new potential therapeutic targets

Trond Ulven. Front Endocrinol (Lausanne). 2012.

Abstract

The deorphanization of the free fatty acid (FFA) receptors FFA1 (GPR40), FFA2 (GPR43), FFA3 (GPR41), GPR84, and GPR120 has made clear that the body is capable of recognizing and responding directly to nonesterified fatty acid of virtually any chain length. Colonic fermentation of dietary fiber produces high concentrations of the short-chain fatty acids (SCFAs) acetate, propionate and butyrate, a process which is important to health. The phylogenetically related 7-transmembrane (7TM) receptors free fatty acid receptor 2 (FFA2) and FFA3 are activated by these SCFAs, and several lines of evidence indicate that FFA2 and FFA3 mediate beneficial effects associated with a fiber-rich diet, and that they may be of interest as targets for treatment of inflammatory and metabolic diseases. FFA2 is highly expressed on immune cells, in particular neutrophils, and several studies suggest that the receptor plays a role in diseases involving a dysfunctional neutrophil response, such as inflammatory bowel disease (IBD). Both FFA2 and FFA3 have been implicated in metabolic diseases such as type 2 diabetes and in regulation of appetite. More research is however required to clarify the potential of the receptors as drug targets and establish if activation or inhibition would be the preferred mode of action. The availability of potent and selective receptor modulators is a prerequisite for these studies. The few modulators of FFA2 or FFA3 that have been published hitherto in the peer-reviewed literature in general have properties that make them less than ideal as such tools, but published patent applications indicate that better tool compounds might soon become available which should enable studies critical to validate the receptors as new drug targets.

Keywords: 7TM receptors; GPCR; free fatty acids; inflammation; metabolic diseases; short-chain fatty acids; type 2 diabetes.

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Figures

Figure 1

Figure 1

SCFAs and other small carboxylic acid modulators of FFA2 and FFA3. pEC50 values of 2–7 for FFA2/FFA3 are from a dynamic mass redistribution assay (Schmidt et al., 2011).

Figure 2

Figure 2

Snake plot of the human FFA2. Residues with black letters are conserved between hFFA2 and hFFA3. Residues in black circles are conserved between hFFA2 and hFFA1. Highlighted hFFA2 residues are identified in the connected squares, the corresponding residues of hFFA3 and hFF1 are given in parenthesis, and Schwartz-Baldwin (Rosenkilde et al., 2010) and Ballesteros-Weinstein (Ballesteros and Weinstein, 1995) notations for TM residue positions are indicated. The most conserved residue of each helix throughout family A of the 7TM receptors are blue. The two arginines and the histidine critical for recognition of SCFAs in FFA2 (R180, H242, R255) and FFA3 (R185, H245, R258) are red and the histidine important for SCFA recognition in FFA2 (H140) and critical in FFA3 (H146) is orange (Stoddart et al., 2008a). The three residues that reverse the selectivity for 4 and 5 when swapped (FFA2: E166L, L183M, C184A; FFA3: L171E, M188L, A189C) are yellow (Schmidt et al., 2011). The cysteine that enables hFFA2 to be activated by longer FFAs when mutated to glycine is green (Hudson et al., 2012).

Figure 3

Figure 3

Selective allosteric agonists of FFA2 (Amgen). Activities from an aequorin-based calcium assay are given (Lee et al., 2008).

Figure 4

Figure 4

FFA2 agonists (Euroscreen). The EC50 values are from GTPγS binding in a scintillation proximity assay (Hoveyda et al., 2010, 2011a,b,c,d).

Figure 5

Figure 5

FFA2 antagonists (Euroscreen and Galapagos). The IC50 value of 17 is from a GTPγS assay in CHO cells expressing FFA2 using propionate (600 μM) as agonist (Brantis et al., 2011). The IC50 value of 18 reflects a calcium mobilization assay and a GTPγS assay (Saniere et al., 2012).

Figure 6

Figure 6

FFA3 modulators (Arena) (Leonard et al., 2006).

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