Introduction The onset of uterine labor is
The onset of uterine labor is the culmination of a gradual uterine activation wherein physiological inflammation induces a common prolabor pathway characterized by increased myometrial contractility, weakening of fetal membrane integrity, and cervical ripening. Pathological proinflammatory stimuli, as observed in numerous etiologies of preterm birth (PTB), can induce ≥1 of the components of this common pathway resulting in preterm labor and is sufficiently pronounced to induce fetal/neonatal damage as has often been reported1, 2; PTB is a leading cause of neonatal mortality and morbidity worldwide.3, 4, 5
During labor metabolic demand increases beyond tissue oxygenation capacity. To sustain the vigorous contractions of the myometrium, glycogen and glucose are utilized by myometrial smooth muscle cells (mSMC) to produce ATP under relative anaerobic conditions, leading to the accumulation of intermediates of carbohydrate metabolites, including lactate. This anaerobic glycolytic metabolic pathway is extremely active (high lactate/pyruvate ratio) in myometrium during labor. Accordingly, blood lactate levels of laboring women increase considerably as a function of the duration of labor.
Lately, lactate has been demonstrated to activate a G protein-coupled receptor, GPR81 (also labeled HCA1). This suggests that lactate has unexpected signaling functions beyond its traditional metabolic role. Along these lines, a role for lactate in the regulation of inflammation has been reported wherein lactate-induced stimulation of GPR81 in leukocytes specifically inhibited the inflammasome, an important proinflammatory system active during labor; correspondingly, a tocolytic function for lactate has been postulated. We thus proceeded to study the role of lactate and GPR81 in the uterus during labor. Herein, we describe a novel role for lactate in regulating inflammation during labor via activation of GPR81 in the uterus.
Materials and Methods
Introduction GPR81 is 52% identical to the nicotinic Oligomycin Complex synthesis receptor GPR109a at the amino acid level and belongs to the same subfamily of receptors as GPR109a and GPR109b (Ahmed et al., 2009, Blad et al., 2011). GPR81 was considered an orphan G-protein-coupled receptor (GPCR) until lactate was recently identified as an endogenous ligand for the receptor (Cai et al., 2008, Liu et al., 2009). GPR81 mediates the inhibitory regulation of lipolysis in adipocytes in response to lactate stimulation by coupling to the Gαi-protein and is highly expressed in brown and white adipose tissue (WAT) in a manner similar to that of GPR109a (Ge et al., 2008, Liu et al., 2009, Wise et al., 2003). This suggests that GPR81 is a potential drug target for treating dyslipidemia. Clinically, the GPR109a agonist nicotinic acid is effective in treating dyslipidemia (Jacobson, 2010). The therapeutic benefits of nicotinic acid are generally exerted by GPR109a-mediated inhibition of lipolysis in adipocytes, which results in reduction in the plasma free fatty acid (FFA) content, thereby contributing to reduction in VLDL and triglycerides (Offermanns, 2006, Pike and Wise, 2004). Despite the advantages of nicotinic acid in treating dyslipidemia, its clinical value is limited because of the major side effect: “flushing” (Benyo et al., 2005, Jacobson, 2010, Pike, 2005, Pike and Wise, 2004). Thus, development of therapeutic agents that maintain the efficacy of nicotinic acid but are not limited by the associated side effects could significantly improve the treatment of dyslipidemia. It has been recently reported that the release of prostaglandin D2 in dendritic Langerhans cells in response to GPR109a activation is responsible for flushing (Benyo et al., 2006, Benyo et al., 2005, Cheng et al., 2006). Thus, in considering the development of novel antidyslipidemia agents without associated flushing, it is of note that the expression of GPR81 is primarily restricted to adipocytes with only minor expression in other tissues. These findings suggest that GPR81 agonists may be potential agents for treating dyslipidemia, with fewer side effects than nicotinic acid.