br Conclusion and future perspectives The
Conclusion and future perspectives The nicotinic Zinc Pyrithione receptor GPR109A and its close relatives GPR109B and GPR81 are primarily expressed in adipocytes and are coupled to Gi-type G proteins. Recently, the ketone body β-hydroxy-butyrate, the β-oxidation intermediate 3-hydroxy octanoic acid and lactate have been identified as endogenous ligands of these receptors. These ligands have in common that they are hydroxylated carboxylic acids for which plasma levels are subject to considerable changes depending on the metabolic state of the organism. Under various physiological and pathophysiological conditions, their plasma concentrations reach levels sufficient to activate the receptors and to inhibit lipolysis. Thereby, the receptors function as metabolic sensors to fine-tune the regulation of lipolytic activity in adipose tissue. In the future it will be interesting to explore the potential role of these receptors in metabolic disorders such as diabetes mellitus, dyslipidemia and obesity. In this regard, it will be important to search for other endogenous metabolic ligands of these receptors which might have remained elusive owing to their low concentration in body fluids. As GPR109A is the receptor for the established antidyslipidemic drug nicotinic acid, GPR109B and in particular GPR81 represent promising drug targets which can have advantages compared to GPR109A. The further development of subtype-specific and more potent ligands of this receptor family would be an important prerequisite to further evaluate these receptors as potential targets for new therapeutic strategies.
When organ injury occurs in the absence of an adequate oxygen supply, the glucose metabolism for energy generation is diverted to lactate, rather than pyruvate, and serum lactate levels rise. Any clinician regards this as an ominous sign for the patient's prognosis and suspect behind rising lactate levels organ ischemia or microcirculatory failure of some sort. He or she will also be aware that this is often paralleled by progressive acidification (a falling pH) and systemic inflammation. Recent cell biological studies have, indeed, suggested that lactate has a direct pro-inflammatory effect on the Toll-like receptor (TLR)/nuclear factor (NF)-κB/inflammasome signaling cascade that ultimately drives systemic inflammation via the activation of interleukin (IL)–1β., Acute liver injury and acute pancreatitis are often associated with significant fluid loss into the interstitial space and affected patients accordingly require large intravenous fluid volumes for replacement. For pancreatitis, a recent randomized clinical trial has unequivocally shown that Ringer lactate solution is much superior to saline infusion when used as a fluid replacement therapy. This seems to contradict the first statement on the negative role and harmful effects of lactate in systemic inflammation and organ failure. Hoque et al now provide an explanation for this apparent paradox in an elegant experimental study in this issue of . They focused their investigation on macrophages/monocytes, which are known to be critically involved in liver and pancreatic inflammation, and used animal disease models for hepatitis (lipopolysaccharide [LPS] and -galactosamine) and pancreatitis (LPS and cerulein) to test their hypothesis that lactate has anti-inflammatory effects and mediates them through a recently discovered lactate receptor, the plasma membrane Gi protein-coupled receptor 81 (GPR81). The authors found that low concentrations of lactate reduce organ injury in both disease models via binding to GPR81. In vitro and in vivo they could show that lactate signaling in macrophages/monocytes is dependent on GPR81 and its adaptor protein ARRB2, and that small interfering RNA blockage of the expression of either protein can regulate this process. Moreover, through this signaling pathway lactate directly inhibited the action of the NLRP3 inflammasome, which is activated via TLR-4 and the action of caspase 1. The consequences were a reduced NF-κB action and diminished conversion of pro–IL-1β to active IL-1β—with a significant beneficial effect on disease severity in both models. Simply put: Lacate at physiologic concentrations is a terrific anti-inflammatory agent and one with proven efficiency not only in human disease but also in experimental models of inflammation.