It has been proposed that HCA may be
It has been proposed that HCA1 may be a better target than HCA2 to treat dyslipidemia and to prevent progression of atherosclerosis, because HCA1 is less widely expressed, and HCA1 activation does not result in flushing. However, since the antilipolytic effects mediated by HCA2 appear to be not the major mediator of the antiatherogenic effects of nicotinic acid, this concept is not followed any more. It remains to be seen whether agonism of HCA1 and HCA2 resulting in antilipolytic effects can be used to treat type 2 diabetes . There is preliminary data supporting a role of HCA1 in the progression of tumor growth 77, 78, 79 as well as in promoting diet-induced obesity . It will therefore be interesting to see whether antagonists of HCA1 could be used to prevent or treat these disorders.
Conclusions and Perspectives HCA receptors are metabolite receptors that contribute to body homeostasis by allowing particular intermediates of energy metabolism to regulate metabolic, immune, and other functions. The lactate receptor, HCA1/GPR81, plays localized roles in the regulation of adipocyte cAMP levels, thereby controlling lipolysis. It is also possible that HCA1 regulates the ability of white and brown adipocytes to produce heat, a mechanism that still needs to be analyzed (see Outstanding Questions). Recently, evidence has emerged that HCA1 is expressed in various tumors including breast cancer and that it can regulate tumor cell survival as well as tumor angiogenesis. Given the high lactate concentration in tumors, it appears plausible that HCA1 affects tumor progression, but more in vivo data using appropriate models are required to define the role of HCA1 in tumors. HCA2/GPR109A and probably also HCA3/GPR109B appear to mediate anti-inflammatory and antilipolytic effects in response to metabolites that are increased during food shortage. Thereby, these receptors may help preserve energy by balancing pro-lipolytic influences and reducing inflammation-induced increases in energy expenditure. HCA2, in addition, appears to mediate the effects of microbiota-derived butyrate on the intestinal system. It is, however, not clear to which degree HCA2 synergizes with other short-chain fatty Pyrimethamine receptor receptors such as FFA2 and FFA3, which are also expressed in the intestinal system. HCA receptor activation may also be involved in preventing and treating various diseases. While HCA2 is an established target for drugs like nicotinic acid, which have antidyslipidemic and antiatherogenic effects, activation of HCA2 may have additional anti-inflammatory and immunomodulatory effects that have not been explored yet, but warrant further investigation. In addition, HCA1 antagonists may be of interest as agents against diet-induced obesity, and they should be tested as agents to reduce tumor growth directly or through indirect effects on the tumor stroma. However, no HCA1 antagonists are yet available to test these concepts, and it remains to be seen whether synthetic HCA1 antagonists can be developed. Finally, an understanding of the role of HCA3, which is expressed only in humans and a few other higher primates, is lagging far behind due to a lack of available animal models. Future work is required to understand the function of HCA3 in humans and to explore whether it is of use as a drug target with advantages compared to HCA2.
Introduction The bovinea subfamily, which include domestic cattle as well as buffalo species, are raised under intensive management systems to maximize milk and meat production worldwide. Improvements in genetic selection and higher nutritional requirements in bovids are factors associated with a higher incidence of several pathologies, including endometritis (LeBlanc, 2012), mastitis (Gomes et al., 2016), acute aseptic lameness (Thoefner et al., 2005) and polysynovitis (Danscher et al., 2010). These diseases have been associated with the metabolic imbalance of a myriad of compounds in the past, including fatty acids and hydroxycarboxylic acids. Metabolic dysfunction is strongly linked to the host innate immune response involving leukocyte and endothelial cell activation in different mammals, including humans. In cattle, several metabolic disorders are associated with acute inflammatory processes, with polymorphonuclear neutrophils (PMN) being one of the main targets, thereby reducing the first line of defense against invasive pathogens. Activated PMN are known to migrate toward a gradient of chemical messengers [i.e., chemoattractants, such as C-X-C motif chemokine ligand 8 (CXCL8)] at sites of infection and sterile inflammation, produced by other host cells and microorganisms (Wang et al., 2009a). Activated PMN might results in pathogen killing (e.g. bacteria, viruses, fungi, parasites) through three different effector mechanisms: production of reactive oxygen species (ROS), phagocytosis/degranulation and neutrophil extracellular traps (NETs) formation (Kolaczkowska and Kubes, 2013). However, excessive PMN activation, especially surrounding healthy tissues, is known to be harmful to the host and may lead to inflammatory processes, even in the absence of microorganisms.