3-Hydroxy octanoic acid

The hydroxy-carboxylic acid (HCA) receptors HCA(1), HCA(2), and HCA(3) were previously known as GPR81, GPR109A, and GPR109B, respectively, or as the nicotinic acid receptor family. They form a cluster of G protein-coupled receptors with high sequence homology. Recently, intermediates of energy metabolism, all HCAs, have been reported as endogenous ligands for each of these receptors. The HCA receptors are predominantly expressed on adipocytes and mediate the inhibition of lipolysis by coupling to G(i)-type proteins. HCA(1) is activated by lactate, HCA(2) by the ketone body 3-hydroxy-butyrate, and HCA(3) by hydroxylated β-oxidation intermediates, especially 3-hydroxy-octanoic acid. Both HCA(2) and HCA(3) are part of a negative feedback loop which keeps the release of fat stores in check under starvation conditions, whereas HCA(1) plays a role in the antilipolytic (fat-conserving) effect of insulin. HCA(2) was first discovered as the molecular target of the antidyslipidemic drug nicotinic acid (or niacin). Many synthetic agonists have since been designed for HCA(2) and HCA(3), but the development of a new, improved HCA-targeted drug has not been successful so far, despite a number of clinical studies. Recently, it has been shown that the major side effect of nicotinic acid, skin flushing, is mediated by HCA(2) receptors on keratinocytes, as well as on Langerhans cells in the skin. In this chapter, we summarize the latest developments in the field of HCA receptor research, with emphasis on (patho)physiology, receptor pharmacology, major ligand classes, and the therapeutic potential of HCA ligands.

Kazakh cheese is a traditional dairy product in Xinjiang, China. To study the function and potential probiotic characteristics of yeast in Kazakh cheese and its contribution to cheese fermentation, we screened the γ-aminobutyric acid (GABA)-producing yeasts Pichia kudriavzevii 1-21, Kluyveromyces marxianus B13-5, Saccharomyces cerevisiae DL6-20, and Kluyveromyces lactis DY1-10. We investigated the potential probiotic properties of these strains and their use in cheese fermentation (cheeses designated CSP, CSM, CSS, and CSI, respectively); a control with no added yeast was designated CS. The results showed that the 4 yeast strains all showed high self-polymerization (2- and 24-h autoaggregation capacity of >80 and 90%, respectively), hydrophobicity (40-92% variation, low hydrophobicity in xylene, but within the range of probiotics), and the ability to survive the gastrointestinal tract (survival rate >75% after simulation), indicating the probiotic ability of the strains in vitro. The GABA production capacity of the CSM cheese increased (to 95.6 mg/100 g), but its protein content did not change significantly, and amino acid degradation was obvious. The GABA production capacity of the CSS cheese decreased (to 450 mg/kg); its protein content declined, and its amino acid content increased. Except for water and protein, we found no obvious differences in most physical and chemical indicators. Kluyveromyces marxianus B13-5 helped to form the desired texture. Multivariate statistical analysis showed that fermentation of the cheese with the 4 yeasts improved the production of esters and alcohols. The CSS cheese had good aroma production performance, because S. cerevisiae DL6-20 produced high concentrations of isoamyl alcohol, hexanoic acid ethyl ester, benzyl alcohol, octanoic acid ethyl ester, 3-hydroxy-2-butanone, and hexanoic acid; the content of 2-methyl-propanoic acid was low. Compared with the CSP cheese, the CSI and CSM cheeses had a fruitier aroma and a milder odor, but the CSI and CSM cheeses had high concentrations of ethyl acetate, butanoic acid, ethyl ester, 3-methyl-1-butanol-acetate, ethyl hexanoate, ethyl octanoate, acetic acid 2-phenylethyl ester, and ethyl lactate; concentrations of 3-methyl-butanoic acid, propanoic acid, acetic acid, and butanoic acid were low. The CSP cheese had stronger acid-producing ability. The order of fragrance production performance was CSS > CSI, CSM > CSP > CS. Research into the fermentation mechanisms of GABA-producing yeast in cheese will provide a theoretical basis for the quality control and industrial production of Kazakh cheese.

In the recent past, deorphanization studies have described intermediates of energy metabolism to activate G protein-coupled receptors and to thereby regulate metabolic functions. GPR81, GPR109A, and GPR109B, formerly known as the nicotinic acid receptor family, are encoded by clustered genes and share a high degree of sequence homology. Recently, hydroxy-carboxylic acids were identified as endogenous ligands of GPR81, GPR109A, and GPR109B, and therefore these receptors have been placed into a novel receptor family of hydroxy-carboxylic acid (HCA) receptors. The HCA(1) receptor (GPR81) is activated by the glycolytic metabolite 2-hydroxy-propionic acid (lactate), the HCA(2) receptor is activated by the ketone body 3-hydroxy-butyric acid, and the HCA(3) receptor (GPR109B) is a receptor for the β-oxidation intermediate 3-hydroxy-octanoic acid. While HCA(1) and HCA(2) receptors are present in most mammalian species, the HCA(3) receptor is exclusively found in humans and higher primates. HCA receptors are expressed in adipose tissue and mediate anti-lipolytic effects in adipocytes through G(i)-type G protein-dependent inhibition of adenylyl cyclase. HCA(2) and HCA(3) inhibit lipolysis during conditions of increased β-oxidation such as prolonged fasting, whereas HCA(1) mediates the anti-lipolytic effects of insulin in the fed state. As HCA(2) is a receptor for the established anti-dyslipidemic drug nicotinic acid, HCA(1) and HCA(3) also represent promising drug targets and several synthetic ligands for HCA receptors have been developed. In this article, we will summarize the deorphanization and pharmacological characterization of HCA receptors. Moreover, we will discuss recent progress in elucidating the physiological and pathophysiological role to further evaluate the therapeutic potential of the HCA receptor family for the treatment of metabolic disease.