br Mutagenesis and Receptor Modeling Studies br

Mutagenesis and Receptor-Modeling Studies
Signal Transduction and Receptor Desensitization
Therapeutic Potential of HCA Receptor Ligands Although all members of the HCA receptor family are potentially interesting drug targets, only HCA2 is currently exploited as such. Therefore, this section will focus on this receptor alone.
Conclusion The first steps toward understanding the physiological relevance of the HCA receptor family have only recently been taken. These receptors seem to have evolved to recognize hydroxylated intermediates of energy metabolism with a relatively low affinity in order to regulate lipolysis. HCA1 seems to contribute to insulin-induced antilipolysis and also to the weight gain induced by a hypercaloric diet. HCA2 is important for the conservation of adipose tissue under starvation conditions, next to its pharmacological role as the high-affinity nicotinic 5 of 17000 receptor. HCA3 seems to be part of the same negative feedback loop to limit lipolysis during starvation. HCA2 and HCA3 may have additional roles in the immune system, but further studies are needed in that area. Despite rather spectacular effects on lipid levels and also on atherosclerosis progression, and the introduction of reduced-flushing formulations, the use of the antidyslipidemic drug nicotinic acid is still stunted by its side effects. Other HCA2 ligands, including partial agonists and biased agonists, may be better tolerated. However, despite extensive efforts of the pharmaceutical industry, no new HCA2 ligands have been successful as clinical candidates so far. More research is needed to enable the identification of genuinely promising molecules. Possibly the most important enigma is how nicotinic acid induces HDL elevation. Recent animal experiments suggest that nicotinic acid reduces the progression of atherosclerosis also via lipid-independent anti-inflammatory effects and by increasing cholesterol efflux from plaque macrophages. Lipid-independent beneficial effects of nicotinic acid, in particular, anti-inflammatory effects, deserve further analysis in the future. HCA1 also has potential as a drug target for antilipolysis, and it is very unlikely that agonists for this receptor cause flushing because no skin expression has been detected. HCA1 antagonists may reduce weight gain, but no antagonists are known to date for any of the HCA receptors. Thus, studies in animals have revealed unexpected physiological and pharmacological roles of HCA receptors. Much more work on the generation of new agonistic and antagonistic ligands of HCA receptors and their analysis in in vitro and in vivo models is required to explore all options to harness HCA receptors as targets to prevent and treat a variety of diseases like dyslipidemia, adipositas, cardiovascular diseases, or chronic inflammatory and immune diseases.
Acknowledgments
Conflict of Interest: The authors have no conflict of interest to declare.
Introduction Classically, lactate has been regarded as a glycolytic waste product after exercise or as a substrate for hepatic gluconeogenesis. Recently, lactate has been drawing attention as an important intermediate metabolite exerting various effects on metabolism. Lactate is produced from glucose through glycolysis and the conversion of pyruvate by lactate dehydrogenase. Skeletal muscle and adipose tissues have been thought to play important roles in supplying lactate. Skeletal muscle is a major production site of lactate. It continuously generates and uses lactate in resting states and, furthermore, lactate production increases during exercise [1]. Adipose tissue is also a source of the lactate supply [2]. Depending on stimulation of the process by insulin and glucose uptake, adipose can convert more than 50% of the lactate metabolized from glucose [3], [4], [5]. Adipose tissue secretes various adipokines, which regulate metabolism. Lactate has been speculated to play an important role as an adipokine secreted from adipocytes, through its receptor G protein-coupled receptor 81 (GPR 81), functioning against the suppression of lipolysis in adipocytes by insulin [6], [7]. In addition, lactate contributes to brain protection in hypoglycemic states, through the cellular interaction between astrocytes and neurons [8], [9]. Furthermore, it has also been noted that lactate may contribute to the browning of white adipose cells via increased uncoupling protein 1 (UCP1) gene expressions [10]. Also, lactate reportedly exerted anti-inflammatory effects in acute hepatitis and acute pancreatitis models [11].