Lactate as administered in these

Lactate as administered in these models is metabolized rapidly and it appears that transient engagement of GPR81 with lactate serum concentrations in the range of moderate exercise physiology, as measured here at 3–4 mmol/L, are sufficient to suppress tissue macrophage NF-κB activation in our models of fulminant hepatitis and severe acute hepatitis (Figure 7) without inducing measurable liver, muscle, or kidney injury (Supplementary Figure 4). Prolonged exposure to supraphysiologic concentrations of lactate can induce intracellular acidosis, which itself can augment NLRP3-mediated responses, and may account for the findings of increased inflammatory responses in prior studies in vitro. In addition, prolonged increases in serum lactate levels are often a marker of significant ischemic injury and any specific benefit of increased serum lactate levels may be overshadowed in this setting by the many proinflammatory signals released by injured TAK 165 in ischemic tissue and by intracellular acidosis. The role of lactate and GPR81 signaling in other innate immune effector cell types remains to be investigated intensely. Human neutrophils express GPR81 and human peripheral blood polymorphonuclear cells have minimal alterations of LPS-induced proinflammatory gene transcription in response to 15 mmol/L lactate (Supplementary Figure 9).
Acknowledgments
Introduction Traditionally, classic hormones and neurotransmitters have been regarded as the quintessential endogenous G-protein-coupled receptor (GPCR) agonists. However, the deorphanization efforts of the past two decades have revealed that GPCRs are activated by many other endogenous diffusible molecules such as ions or metabolites. Recently, a subfamily of GPCRs consisting of GPR81, GPR109A and GPR109B has emerged as a new group of metabolite receptors. GPR109A, GPR109B and GPR81 by homology represent a subfamily of GPCRs (Figure 1), and their genes most probably evolved by duplication as indicated by their tandem location on human chromosome 12q24. GPR109B (HM74), which is found only in higher primates, and GPR81 were originally identified as orphan GPCRs 1, 2, whereas GPR109A was first described in mice as a “protein upregulated in macrophages by interferon γ” [3]. In 2003, several groups identified GPR109A as the receptor of the antidyslipidemic drug nicotinic acid 4, 5, 6. Using a mouse knockout model, GPR109A was demonstrated to be responsible for the antilipolytic and triglyceride-lowering effects of nicotinic acid as well as for the major side effects of nicotinic acid, a cutaneous vasodilation called flushing 5, 7. The ketone body 3-hydroxy-butyrate was identified as an endogenous ligand of GPR109A [8]. More recently, GPR81 was shown to be activated by lactate 9, 10, whereas GPR109B is a receptor for 3-hydroxylated β-oxidation intermediates, in particular 3-hydroxy-octanoate [11] (Table 1). Here, we briefly summarize current knowledge on members of this GPCR subfamily which function as metabolic sensors being activated by intermediates of energy metabolism. We propose that this receptor subfamily is defined by the hydroxy-carboxylic acid structure of its endogenous ligands.
Pharmacology The discovery of GPR109A as a receptor for the antidyslipidemic drug nicotinic acid has included this receptor and its relatives GPR109B and GPR81 as part of many pharmaceutical research programs, and many new synthetic ligands with activity on this receptor family have been developed. In addition to nicotinic acid, acipimox, a drug with pharmacological effects similar to those of nicotinic acid as well as monomethylfumarate, an antipsoriatic drug, and a variety of newly synthesized compounds have been shown to be selective GPR109A agonists 12, 13, 14. Several groups have developed partial agonists for GPR109A such as derivatives of pyrazole-3-carboxylic acid or cyclopentapyrazole (MK-0354) 15, 16, 17. Recently, allosteric agonists of GPR109A have been generated [18]. Also, selective agonists for GPR109B have been described such as 1- and 2-substituted benzotriazole-5-carboxylic acids, 6-amino nicotinic acids and benzoic acid derivatives as well as 5-N,N-disubstituted 5-amino-pyrazole-3-carboxylic acids 19, 20, 21. It has recently been shown that aromatic D-amino acids are specific agonists of GPR109B [22]. Given the extreme rare occurrence of D-amino acids, it is unclear whether the ability of aromatic D-amino acids to activate GPR109B is of physiological significance. There are also synthetic ligands which are able to activate both GPR109A and GPR109B 6, 23.