Trends in Endocrinology & Metabolism
ReviewHydroxy-Carboxylic Acid Receptor Actions in Metabolism
Introduction
Many nutrients and intermediates of energy metabolism are not only carriers of energy but also function as signaling molecules which modulate metabolic, immune, and other functions in the mammalian organism by activating specific receptors. While nuclear receptors have long been known to play important roles in mediating effects of metabolites 1, 2, more recently various G protein-coupled receptors have also been shown to be activated by metabolic intermediates [3]. Prominent examples are the hydroxy-carboxylic acid (HCA) receptors. The HCA receptor family consists of three members, HCA1, HCA2, and HCA3, also known as GPR81, GPR109A, and GPR109B, respectively, which are encoded by closely related genes [4]. The physiological ligands of HCA receptors are key metabolic intermediates whose local and systemic levels reflect particular metabolic states. Lactic acid, the end product of glycolysis, activates HCA1, whereas the ketone body 3-hydroxy-butyric acid [β-hydroxybutyrate (β-HB)] and the β-oxidation intermediate 3-hydroxy-octanoic acid activate HCA2 and HCA3, respectively. In addition, HCA2 is also activated by butyric acid. HCA receptors have relatively low affinities for their natural ligands, however, in some cases, synthetic ligands with increased affinity have been developed [4]. In addition, drugs such as nicotinic acid and dimethyl fumarate (DMF) have been shown to exert at least part of their pharmacological activity through the receptor HCA2 4, 5, 6. The pharmacological properties of HCA receptors have recently been summarized by several reviews 4, 7. This review will focus on the physiological and pathophysiological functions, as well as on the therapeutic potential of this receptor family.
Section snippets
General Properties of HCA Receptors
The genes encoding the three HCA receptors are located next to each other on human chromosome 12 and mouse chromosome 5. HCA1 is the phylogenetically oldest receptor, found already in fish [8]. By contrast, functionally active HCA2 receptors appear to be restricted to mammals, and the HCA3 receptor has only been found in higher primates [9]. Consistent with the close genetic relationship of the genes encoding the three receptors, their main physiological ligands also show structural similarity,
HCA Receptors in the Adipose Tissue
All three HCA receptors are highly expressed in white and brown adipocytes. Expressions of HCA1 and HCA2 have been shown to increase during differentiation of adipocytes from preadipocytes as well as after activation of peroxisome proliferator-activated receptor-gamma 11, 17, 18. Both high-fat diet (HFD) feeding and exposure to various inflammatory stimuli result in decreased expression of HCA1 in the adipose tissue 31, 32. While HCA2 expression in the adipose tissue is also decreased after HFD
HCA2: Therapeutic Target for Atherosclerosis and Neuroinflammatory Conditions?
Parallel to the reports suggesting that the antilipolytic effects mediated by HCA2 are not responsible for the antiatherogenic activity of nicotinic acid, evidence emerged that nicotinic acid can reduce the progression of atherosclerosis independently from changes in plasma lipid levels 54, 55, and that these effects are mediated by activation of HCA2 in bone marrow-derived cells [54]. The antiatherogenic and anti-inflammatory effects of nicotinic acid were accompanied by a reduced infiltration
HCA2 As a Mediator of High-Fiber Diet Effects
Dietary fibers have multiple beneficial effects on the intestinal homeostasis and beyond. Many of these effects are believed to be due to the fermentation of fibers by microbiota of the gut, which results in the formation of short-chain fatty acids such as acetate, propionate, and butyrate [70]. Among the short-chain fatty acids, butyrate has been most intensively studied. It is present in millimolar concentrations in the gut lumen, serves as an energy source for colonocytes, has
Other Functions of HCA Receptors
HCA receptors, in particular HCA1, are expressed in various primary tumor cells 77, 78, 79. This is of interest, as most solid tumors show increased glucose uptake and lactate formation even under normoxic conditions, with lactate concentrations in the tumor microenvironment as high as 30 mM [80], sufficient to activate HCA1. Several in vitro studies showed that inhibition or suppression of HCA1 activation can result in reduced survival of tumor cells. Various mechanisms have been proposed to
Therapeutic Potential
The ketone body receptor HCA2 is already a well-established target for several drugs, including nicotinic acid and other antidyslipidemic/antiatherogenic compounds, as well as the monomethyl fumarate precursor DMF that is being used to treat psoriasis and relapsing multiple sclerosis 63, 88. The clinical efficacies of nicotinic acid and DMF have been described before, and HCA2 was recognized as a critical mediator of their effects. It therefore appears possible that the full potential of HCA2
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,
Acknowledgments
The excellent secretarial help of Svea Hümmer is greatly appreciated. The author's own work was supported by the German Research Foundation and the Max Planck Society.
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