Review
Hydroxy-Carboxylic Acid Receptor Actions in Metabolism

https://doi.org/10.1016/j.tem.2016.11.007Get rights and content

Trends

Lactate activates HCA1 on adipocytes in an autocrine manner. It inhibits lipolysis and thereby promotes anabolic effects. Blockade of HCA1 may prevent and treat obesity.

HCA2 and HCA3 regulate adipocyte lipolysis and immune functions under conditions of increased FFA formation through lipolysis (e.g., during fasting). HCA2 agonists acting mainly through the receptor on immune cells exert antiatherogenic and anti-inflammatory effects.

HCA2 is a receptor for butyrate and mediates some of the beneficial effects of short-chain fatty acids produced by gut microbiota.

Lactic acid, the ketone body 3-hydroxy-butyric acid, also known as β-hydroxybutyrate, and the β-oxidation intermediate 3-hydroxy-octanoic acid are hydroxy-carboxylic acids (HCAs) that serve as intermediates of energy metabolism. However, they also regulate cellular functions, in part by directly activating the G protein-coupled receptors HCA1/GPR81, HCA2/GPR109A, and HCA3/GPR109B. During the past decade, it has become clear that HCA receptors help to maintain homeostasis under changing metabolic and dietary conditions, by controlling metabolic, immune, and other body functions. Work based on genetic mouse models and synthetic ligands of HCA receptors has, in addition, shown that members of this receptor family can serve as targets for the prevention and therapy of diseases such as metabolic and inflammatory disorders.

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.

References (99)

  • J.B. Regard

    Anatomical profiling of G protein-coupled receptor expression

    Cell

    (2008)
  • D. Maciejewski-Lenoir

    Langerhans cells release prostaglandin D2 in response to nicotinic acid

    J. Invest. Dermatol.

    (2006)
  • G.A. Cresci

    Colonic gene expression in conventional and germ-free mice with a focus on the butyrate receptor GPR109A and the butyrate transporter SLC5A8

    J. Gastrointest. Surg.

    (2010)
  • T. Soga

    Molecular cloning and characterization of prokineticin receptors

    Biochim. Biophys. Acta

    (2002)
  • S. Yousefi

    cDNA representational difference analysis of human neutrophils stimulated by GM-CSF

    Biochem. Biophys. Res. Commun.

    (2000)
  • D. Wanders

    Effects of high fat diet on GPR109A and GPR81 gene expression

    Biochem. Biophys. Res. Commun.

    (2012)
  • P. Arner

    Human fat cell lipolysis: biochemistry, regulation and clinical role

    Best Pract. Res. Clin. Endocrinol. Metab.

    (2005)
  • P. Arner et al.

    Lipolysis in lipid turnover, cancer cachexia, and obesity-induced insulin resistance

    Trends Endocrinol. Metab.

    (2014)
  • A.K. Taggart

    (d)-β-Hydroxybutyrate inhibits adipocyte lipolysis via the nicotinic acid receptor PUMA-G

    J. Biol. Chem.

    (2005)
  • M. Hernandez

    Critical role of cholesterol ester transfer protein in nicotinic acid-mediated HDL elevation in mice

    Biochem. Biophys. Res. Commun.

    (2007)
  • P. Morigny

    Adipocyte lipolysis and insulin resistance

    Biochimie

    (2016)
  • R. Dobbins

    GSK256073 acutely regulates NEFA levels via HCA2 agonism but does not achieve durable glycaemic control in type 2 diabetes. A randomised trial

    Eur. J. Pharmacol.

    (2015)
  • L. Chen

    Niacin-induced hyperglycemia is partially mediated via niacin receptor GPR109a in pancreatic islets

    Mol. Cell. Endocrinol.

    (2015)
  • N. Wang

    Niacin receptor GPR109A inhibits insulin secretion and is down-regulated in type 2 diabetic islet beta-cells

    Gen. Comp. Endocrinol.

    (2016)
  • E.C. Graff

    Anti-inflammatory effects of the hydroxycarboxylic acid receptor 2

    Metabolism

    (2016)
  • S. Offermanns et al.

    Nutritional or pharmacological activation of HCA2 ameliorates neuroinflammation

    Trends Mol. Med.

    (2015)
  • L. Kappos

    Efficacy and safety of oral fumarate in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled phase IIb study

    Lancet

    (2008)
  • U. Mrowietz et al.

    Dimethylfumarate for psoriasis: more than a dietary curiosity

    Trends Mol. Med.

    (2005)
  • A. Koh

    From dietary fiber to host physiology: short-chain fatty acids as key bacterial metabolites

    Cell

    (2016)
  • N. Singh

    Activation of Gpr109a, receptor for niacin and the commensal metabolite butyrate, suppresses colonic inflammation and carcinogenesis

    Immunity

    (2014)
  • J. Tan

    Dietary fiber and bacterial SCFA enhance oral tolerance and protect against food allergy through diverse cellular pathways

    Cell Rep.

    (2016)
  • J.A. Menendez

    Fine-tuning the lipogenic/lipolytic balance to optimize the metabolic requirements of cancer cell growth: molecular mechanisms and therapeutic perspectives

    Biochim. Biophys. Acta

    (2010)
  • V. Singh

    Mycobacterium tuberculosis-driven targeted recalibration of macrophage lipid homeostasis promotes the foamy phenotype

    Cell Host Microbe

    (2012)
  • D. Kumar

    Genome-wide analysis of the host intracellular network that regulates survival of Mycobacterium tuberculosis

    Cell

    (2010)
  • N. Agrawal

    Dissecting host factors that regulate the early stages of tuberculosis infection

    Tuberculosis (Edinb)

    (2016)
  • M.S. Engelstoft

    Seven transmembrane G protein-coupled receptor repertoire of gastric ghrelin cells

    Mol. Metab.

    (2013)
  • D. Sprecher

    Discovery and characterization of GSK256073, a non-flushing hydroxy-carboxylic acid receptor 2 (HCA2) agonist

    Eur. J. Pharmacol.

    (2015)
  • P.J. Skinner

    5-N,N-disubstituted 5-aminopyrazole-3-carboxylic acids are highly potent agonists of GPR109b

    Bioorg. Med. Chem. Lett.

    (2009)
  • N.Y. Kalaany et al.

    LXRS and FXR: the yin and yang of cholesterol and fat metabolism

    Annu. Rev. Physiol.

    (2006)
  • C.C. Blad

    G protein-coupled receptors for energy metabolites as new therapeutic targets

    Nat. Rev. Drug Discov.

    (2012)
  • S. Offermanns

    International Union of Basic and Clinical Pharmacology. LXXXII: nomenclature and classification of hydroxy-carboxylic acid receptors (GPR81, GPR109A, and GPR109B)

    Pharmacol. Rev.

    (2011)
  • J. Hanson

    Nicotinic acid- and monomethyl fumarate-induced flushing involves GPR109A expressed by keratinocytes and COX-2-dependent prostanoid formation in mice

    J. Clin. Invest.

    (2010)
  • H.C. Shen et al.

    Novel patent publications on high-affinity nicotinic acid receptor agonists

    Expert Opin. Ther. Pat.

    (2009)
  • C. Kuei

    Study of GPR81, the lactate receptor, from distant species identifies residues and motifs critical for GPR81 functions

    Mol. Pharmacol.

    (2011)
  • C. Zellner

    Variations in human HM74 (GPR109B) and HM74A (GPR109A) niacin receptors

    Hum. Mutat.

    (2005)
  • S. Tunaru

    PUMA-G and HM74 are receptors for nicotinic acid and mediate its anti-lipolytic effect

    Nat. Med.

    (2003)
  • A. Schaub

    PUMA-G, an IFN-gamma-inducible gene in macrophages is a novel member of the seven transmembrane spanning receptor superfamily

    Eur. J. Immunol.

    (2001)
  • Z. Benyo

    GPR109A (PUMA-G/HM74A) mediates nicotinic acid-induced flushing

    J. Clin. Invest.

    (2005)
  • G. Kostylina

    Neutrophil apoptosis mediated by nicotinic acid receptors (GPR109A)

    Cell Death Differ.

    (2008)
  • Cited by (113)

    • The Promise of Niacin in Neurology

      2023, Neurotherapeutics
    View all citing articles on Scopus
    View full text