Niacin receptor 1

Last updated
HCAR2
Identifiers
Aliases HCAR2 , GPR109A, HCA2, HM74a, HM74b, NIACR1, PUMAG, Puma-g, Niacin receptor 1, hydroxycarboxylic acid receptor 2
External IDs MGI: 1933383 HomoloGene: 4391 GeneCards: HCAR2
Gene location (Human)
Ideogram human chromosome 12.svg
Chr. Chromosome 12 (human) [1]
Human chromosome 12 ideogram.svg
HSR 1996 II 3.5e.svg
Red rectangle 2x18.png
Band 12q24.31Start122,701,293 bp [1]
End122,703,343 bp [1]
Orthologs
SpeciesHumanMouse
Entrez

338442

80885

Ensembl

ENSG00000182782

ENSMUSG00000045502

UniProt

Q8TDS4

Q9EP66

RefSeq (mRNA)

NM_177551

NM_030701

RefSeq (protein)

NP_808219

NP_109626

Location (UCSC) Chr 12: 122.7 – 122.7 Mb Chr 5: 123.86 – 123.87 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Hydroxycarboxylic acid receptor 2 (HCA2), also known as niacin receptor 1 (NIACR1) and GPR109A, [5] is a protein which in humans is encoded by the HCAR2 gene. [6] [7] [8] [9]

Protein biological molecule consisting of chains of amino acid residues

Proteins are large biomolecules, or macromolecules, consisting of one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, responding to stimuli, providing structure to cells and organisms, and transporting molecules from one location to another. Proteins differ from one another primarily in their sequence of amino acids, which is dictated by the nucleotide sequence of their genes, and which usually results in protein folding into a specific three-dimensional structure that determines its activity.

Gene Basic physical and functional unit of heredity

In biology, a gene is a sequence of nucleotides in DNA or RNA that codes for a molecule that has a function. During gene expression, the DNA is first copied into RNA. The RNA can be directly functional or be the intermediate template for a protein that performs a function. The transmission of genes to an organism's offspring is the basis of the inheritance of phenotypic trait. These genes make up different DNA sequences called genotypes. Genotypes along with environmental and developmental factors determine what the phenotypes will be. Most biological traits are under the influence of polygenes as well as gene–environment interactions. Some genetic traits are instantly visible, such as eye color or number of limbs, and some are not, such as blood type, risk for specific diseases, or the thousands of basic biochemical processes that constitute life.

Contents

Function

HCA2 is a high-affinity Gi/Go-coupled G protein-coupled receptor (GPCR) for nicotinic acid (niacin), [8] [9] and is a member of the nicotinic acid receptor family of GPCRs. HCA2 activation inhibits lipolytic and atherogenic activity (i.e., it inhibits the breakdown of fats and the development of atherosclerosis), induces vasodilation (i.e., the dilation of blood vessels), and is responsible for niacin-induced flushing. [10]

GNAI1 protein-coding gene in the species Homo sapiens

Guanine nucleotide-binding protein G(i), alpha-1 subunit is a protein that in humans is encoded by the GNAI1 gene.

GNAO1 protein-coding gene in the species Homo sapiens

Guanine nucleotide-binding protein G(o) subunit alpha is a protein that in humans is encoded by the GNAO1 gene.

Atherosclerosis form of arteriosclerosis

Atherosclerosis is a disease in which the inside of an artery narrows due to the build up of plaque. Initially, there are generally no symptoms. When severe, it can result in coronary artery disease, stroke, peripheral artery disease, or kidney problems, depending on which arteries are affected. Symptoms, if they occur, generally do not begin until middle age.

5-oxo-ETE

The mouse ortholog of HCA2, Niacr1, has been proposed to mediate the ability of 5-oxo-ETE, a member of the 5-HETE family of eicosanoids, to stimulate the production of steroidogenic acute regulatory protein mRNA, Steroidogenic acute regulatory protein, and thereby progesterone in mouse cultured MA-10 Leydig cells. [11] Human tissues respond to 5-oxo-ETE and other 5-HETE family members though the OXER1 G protein-coupled receptor. The roles, if any, of Niacr1 in the response of leydig cells to other 5-HETE family members, of Niacr1 in the response of other mouse cells to 5-HETE family members, and the role of HCA2 in the response of human tissues to 5-HETE family members has not been determined.

The steroidogenic acute regulatory protein, commonly referred to as StAR (STARD1), is a transport protein that regulates cholesterol transfer within the mitochondria, which is the rate-limiting step in the production of steroid hormones. It is primarily present in steroid-producing cells, including theca cells and luteal cells in the ovary, Leydig cells in the testis and cell types in the adrenal cortex.

Clinical significance

HCA2 is an important biomolecular target of niacin which is a widely prescribed drug for the treatment of dyslipidemia and to increase HDL cholesterol but whose therapeutic use is limited by flushing. [12] In HCA2 knockout mice, the effects of niacin on both lipids [13] and flushing [14] is eliminated. Furthermore, in arrestin beta 1 knockout mice, niacin's effect on flushing is greatly reduced while the lipid modifying effects are maintained. [15] At high doses, niacin produces marked anti-inflammatory effects in a variety of tissues – including the brain, gastrointestinal tract, skin, and vascular tissue  – through activation of HCA2. [16] [17] [18] [19] Niacin has also been shown to attenuate neuroinflammation in part through NIACR1 binding; [16] consequently, HCA2 has been identified as a potential therapeutic target for treating neuroimmune disorders such as multiple sclerosis and Parkinson's disease. [16] [19]

A biological target is anything within a living organism to which some other entity is directed and/or binds, resulting in a change in its behavior or function. Examples of common classes of biological targets are proteins and nucleic acids. The definition is context-dependent, and can refer to the biological target of a pharmacologically active drug compound, the receptor target of a hormone, or some other target of an external stimulus. Biological targets are most commonly proteins such as enzymes, ion channels, and receptors.

Dyslipidemia is an abnormal amount of lipids in the blood. In developed countries, most dyslipidemias are hyperlipidemias; that is, an elevation of lipids in the blood. This is often due to diet and lifestyle. Prolonged elevation of insulin levels can also lead to dyslipidemia. Likewise, increased levels of O-GlcNAc transferase (OGT) may cause dyslipidemia.

High-density lipoprotein (HDL) is one of the five major groups of lipoproteins. Lipoproteins are complex particles composed of multiple proteins which transport all fat molecules (lipids) around the body within the water outside cells. They are typically composed of 80-100 proteins per particle and transporting up to hundreds of fat molecules per particle.

The precise mechanism of action of niacin therapeutic effects has not been fully elucidated, but appears to work in part through activation of HCA2 which reduces the levels of intracellular cAMP thereby inhibiting lipolysis in adipocytes. [20] In contrast, the flushing effect is due to HCA2 activation of ERK 1/2 MAP kinase [21] mediated by arrestin beta 1. [15] Activation of MAP kinase in turn causes release of prostaglandin D2 from Langerhans cells in the skin. [22]

Cyclic adenosine monophosphate chemical compound

Cyclic adenosine monophosphate is a second messenger important in many biological processes. cAMP is a derivative of adenosine triphosphate (ATP) and used for intracellular signal transduction in many different organisms, conveying the cAMP-dependent pathway. It should not be confused with 5'-AMP-activated protein kinase.

Lipolysis is the metabolic pathway through which lipid triglycerides are hydrolyzed into a glycerol and three fatty acids. It is used to mobilize stored energy during fasting or exercise, and usually occurs in fat adipocytes. Lipolysis is induced by several hormones, including glucagon, epinephrine, norepinephrine, growth hormone, atrial natriuretic peptide, brain natriuretic peptide, and cortisol.

Adipocyte cells that primarily compose adipose tissue, specialized in storing energy as fat

Adipocytes, also known as lipocytes and fat cells, are the cells that primarily compose adipose tissue, specialized in storing energy as fat. Adipocytes are derived from mesenchymal stem cells which give rise to adipocytes, osteoblasts, myocytes and other cell types through adipogenesis.

Ligands

Full agonists of HCA2 include:

Niacin, also known as nicotinic acid, is an organic compound and a form of vitamin B3, an essential human nutrient. It has the formula C
6H
5NO
2 and belongs to the group of the pyridinecarboxylic acid.

Butyric acid carboxylic acid

Butyric acid (from Ancient Greek: βούτῡρον, meaning "butter"), also known under the systematic name butanoic acid, is a carboxylic acid with the structural formula CH3CH2CH2-COOH. Salts and esters of butyric acid are known as butyrates or butanoates. Butyric acid is found in animal fat and plant oils, bovine milk, breast milk, butter, parmesan cheese, and as a product of anaerobic fermentation (including in the colon and as body odor). Butyric acid has a taste somewhat like butter and an unpleasant odor. Mammals with good scent detection abilities, such as dogs, can detect it at 10 parts per billion, whereas humans can only detect it in concentrations above 10 parts per million. In food manufacturing, it is used as a flavoring agent.

Butyrate salt or ester of butyric acid

Butyrate or butanoate is the traditional name for the conjugate base of butyric acid. The formula of the butyrate ion is C
4H
7O−
2. The name is used as part of the name of esters and salts of butyric acid

Related Research Articles

<i>beta</i>-Hydroxybutyric acid group of enantiomers

β-Hydroxybutyric acid, also known as 3-hydroxybutyric acid, is an organic compound and a beta hydroxy acid with the chemical formula CH3CH(OH)CH2CO2H; its conjugate base is β-hydroxybutyrate, also known as 3-hydroxybutyrate. β-Hydroxybutyric acid is a chiral compound with two enantiomers: D-β-hydroxybutyric acid and L-β-hydroxybutyric acid. Its oxidized and polymeric derivatives occur widely in nature. In humans, D-β-hydroxybutyric acid is one of two primary endogenous agonists of hydroxycarboxylic acid receptor 2 (HCA2), a Gi/o-coupled G protein-coupled receptor (GPCR).

Most of the eicosanoid receptors are integral membrane protein G protein-coupled receptors (GPCRs) that bind and respond to eicosanoid signaling molecules. Eicosanoids are rapidly metabolized to inactive products and therefore are short-lived. Accordingly, the eicosanoid-receptor interaction is typically limited to a local interaction: cells, upon stimulation, metabolize arachidonic acid to an eicosanoid which then binds cognate receptors on either its parent cell or on nearby cells to trigger functional responses within a restricted tissue area, e.g. an inflammatory response to an invading pathogen. In some cases, however, the synthesized eicosanoid travels through the blood to trigger systemic or coordinated tissue responses, e.g. prostaglandin (PG) E2 released locally travels to the hypothalamus to trigger a febrile reaction. An example of a non-GPCR receptor that binds many eicosanoids is the PPAR-γ nuclear receptor.

Acipimox chemical compound lipid-lowering agent

Acipimox is a niacin derivative used as a lipid-lowering agent. It reduces triglyceride levels and increases HDL cholesterol. It may have less marked adverse effects than niacin, although it is unclear whether the recommended dose is as effective as standard doses of niacin.

GPER protein-coding gene in the species Homo sapiens

G protein-coupled estrogen receptor 1 (GPER), also known as G protein-coupled receptor 30 (GPR30), is a protein that in humans is encoded by the GPER gene. GPER binds to and is activated by the female sex hormone estradiol and is responsible for some of the rapid effects that estradiol has on cells.

NAGly receptor protein-coding gene in the species Homo sapiens

N-Arachidonyl glycine receptor, also known as G protein-coupled receptor 18 (GPR18), is a protein that in humans is encoded by the GPR18 gene. Along with the other previously "orphan" receptors GPR55 and GPR119, GPR18 has been found to be a receptor for endogenous lipid neurotransmitters, several of which also bind to cannabinoid receptors.

GPR31 protein-coding gene in the species Homo sapiens

G-protein coupled receptor 31 also known as 12-(S)-HETE receptor is a protein that in humans is encoded by the GPR31 gene. The human gene is located on chromosome 6q27 and encodes a G-protein coupled receptor protein composed of 319 amino acids.

GPR32 protein-coding gene in the species Homo sapiens

G protein-coupled receptor 32, also known as GPR32 or the RvD1 receptor, is a human Receptor (biochemistry) belonging to the rhodopsin-like subfamily of G protein-coupled receptors.

Hydroxycarboxylic acid receptor 3 protein-coding gene in the species Homo sapiens

Hydroxycarboxylic acid receptor 3 (HCA3), also known as niacin receptor 2 (NIACR2) and GPR109B, is a protein which in humans is encoded by the HCAR3 gene. HCA3, like the other hydroxycarboxylic acid receptors HCA1 and HCA2, is a Gi/o-coupled G protein-coupled receptor (GPCR). The primary endogenous agonist of HCA3 is 3-hydroxyoctanoic acid. HCA3 is also a low-affinity biomolecular target for niacin (aka nicotinic acid).

GPR75 protein-coding gene in the species Homo sapiens

Probable G-protein coupled receptor 75 is a protein that in humans is encoded by the GPR75 gene.

Hydroxycarboxylic acid receptor 1 protein-coding gene in the species Homo sapiens

Hydroxycarboxylic acid receptor 1 (HCA1), formerly known as G protein-coupled receptor 81 (GPR81), is a protein that in humans is encoded by the HCAR1 gene. HCA1, like the other hydroxycarboxylic acid receptors HCA2 and HCA3, is a Gi/o-coupled G protein-coupled receptor (GPCR). The primary endogenous agonist of HCA1 is lactic acid (and its conjugate base, lactate).

OXGR1 protein-coding gene in the species Homo sapiens

2-Oxoglutarate receptor 1 (OXGR1), also known as cysteinyl leukotriene receptor E (CysLTE) and GPR99, is a protein that in humans is encoded by the OXGR1 gene. The Gene has recently been nominated as a receptor not only for 2-oxogluterate but also for the three cysteinyl leukotrienes (CysLTs), particularly leukotriene E4 (LTE4) and to far lesser extents LTC4 and LTE4. Recent studies implicate GPR99 as a cellular receptor which is activated by LTE4 thereby causing these cells to contribute to mediating various allergic and hypersensitivity responses.

GPR132 protein-coding gene in the species Homo sapiens

G protein coupled receptor 132, also termed G2A, is classified as a member of the proton sensing G protein coupled receptor (GPR) subfamily. Like other members of this subfamily, i.e. GPR4, OGR1 (GPR68), and TDAG8 (GPR65), G2A is a G protein coupled receptor that resides in the cell surface membrane, senses changes in extracellular pH, and can alter cellular function as a consequence of these changes. Subsequently, G2A was suggested to be a receptor for lysophosphatidylcholine (LPC). However, the roles of G2A as a pH-sensor or LPC receptor are disputed. Rather, current studies suggest that it is a receptor for certain metabolites of the polyunsaturated fatty acid, linoleic acid.

GPR120 protein-coding gene in the species Homo sapiens

G-protein coupled receptor 120 is a protein that in humans is encoded by the GPR120 gene.

Oxoeicosanoid receptor 1 protein-coding gene in the species Homo sapiens

Oxoeicosanoid receptor 1 (OXER1) also known as G-protein coupled receptor 170 (GPR170) is a protein that in humans is encoded by the OXER1 gene located on human chromosome 2p21; it is the principle receptor for the 5-Hydroxyicosatetraenoic acid family of carboxy fatty acid metabolites derived from arachidonic acid. The receptor has also been termed hGPCR48, HGPCR48, and R527 but OXER1 is now its preferred designation. OXER1 is a G protein-coupled receptor (GPCR) that is structurally related to the hydroxy-carboxylic acid (HCA) family of G protein-coupled receptors whose three members are HCA1 (GPR81), HCA2, and HCA3 ; OXER1 has 30.3%, 30.7%, and 30.7% amino acid sequence identity with these GPCRs, respectively. It is also related to the recently defined receptor, GPR31, for the hydroxyl-carboxy fatty acid 12-HETE.

5-Hydroxyeicosatetraenoic acid chemical compound

5-Hydroxyeicosatetraenoic acid is an eicosanoid, i.e. a metabolite of arachidonic acid. It is produced by diverse cell types in humans and other animal species. These cells may then metabolize the formed 5(S)-HETE to 5-oxo-eicosatetraenoic acid (5-oxo-ETE), 5(S),15(S)-dihydroxyeicosatetraenoic acid, or 5-oxo-15-hydroxyeicosatetraenoic acid.

12-Hydroxyeicosatetraenoic acid chemical compound

12-Hydroxyeicosatetraenoic acid (12-HETE) is a derivative of the 20 carbon polyunsaturated fatty acid, arachidonic acid, containing a Hydroxyl residue at carbon 12 and a 5Z,8Z,10E,14Z Cis–trans isomerism configuration in its four double bonds. It was first found as a product of arachidonic acid metabolism made by human and bovine platelets through their 12S-lipoxygenase enzyme(s). However, the term 12-HETE is ambiquous in that it has been used to indicate not only the initially detected "S" stereoisomer, 12S-hydroxy-5Z,8Z,10E,14Z-eicosatetraenoic acid, made by platelets, but also the later detected "R" stereoisomer, 12(R)-hydroxy-5Z,8Z,10E,14Z-eicosatetraenoic acid made by other tissues through their 12R-lipoxygenase enzyme, ALOX12B. The two isomers, either directly or after being further metabolized, have been suggested to be involved in a variety of human physiological and pathological reactions. Unlike hormones which are secreted by cells, travel in the circulation to alter the behavior of distant cells, and thereby act as Endocrine signalling agents, these arachidonic acid metabolites act locally as Autocrine signalling and/or Paracrine signaling agents to regulate the behavior of their cells of origin or of nearby cells, respectively. In these roles, they may amplify or dampen, expand or contract cellular and tissue responses to disturbances.

3-Hydroxyoctanoic acid pair of enantiomers

3-Hydroxyoctanoic acid is a beta-hydroxy acid that is naturally produced in humans, other animals, and plants.

5-oxo-eicosatetraenoic acid

5-Oxo-eicosatetraenoic acid is a Nonclassic eicosanoid metabolite of arachidonic acid and the most potent naturally occurring member of the 5-HETE family of cell signaling agents. Like other cell signaling agents, 5-oxo-ETE is made by a cell and then feeds back to stimulate its parent cell and/or exits this cell to stimulate nearby cells. 5-Oxo-ETE can stimulate various cell types particularly human leukocytes but possesses its highest potency and power in stimulating the human eosinophil type of leukocyte. It is therefore suggested to be formed during and to be an important contributor to the formation and progression of eosinophil-based allergic reactions; it is also suggested that 5-oxo-ETE may also contribute inflammation, cancer cell growth, and other pathophysiological responses.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000182782 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000045502 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:".
  4. ↑ "Mouse PubMed Reference:".
  5. ↑ Offermanns S, Colletti SL, Lovenberg TW, Semple G, Wise A, IJzerman AP (June 2011). "International Union of Basic and Clinical Pharmacology. LXXXII: Nomenclature and Classification of Hydroxy-carboxylic Acid Receptors (GPR81, GPR109A, and GPR109B)". Pharmacological Reviews. 63 (2): 269–90. doi:10.1124/pr.110.003301. PMID   21454438.
  6. ↑ Takeda S, Kadowaki S, Haga T, Takaesu H, Mitaku S (June 2002). "Identification of G protein-coupled receptor genes from the human genome sequence". FEBS Letters. 520 (1-3): 97–101. doi:10.1016/S0014-5793(02)02775-8. PMID   12044878.
  7. ↑ "Entrez Gene: GPR109A G protein-coupled receptor 109A".
  8. 1 2 Wise A, Foord SM, Fraser NJ, Barnes AA, Elshourbagy N, Eilert M, Ignar DM, Murdock PR, Steplewski K, Green A, Brown AJ, Dowell SJ, Szekeres PG, Hassall DG, Marshall FH, Wilson S, Pike NB (March 2003). "Molecular identification of high and low affinity receptors for nicotinic acid". The Journal of Biological Chemistry. 278 (11): 9869–74. doi:10.1074/jbc.M210695200. PMID   12522134.
  9. 1 2 Soga T, Kamohara M, Takasaki J, Matsumoto S, Saito T, Ohishi T, Hiyama H, Matsuo A, Matsushime H, Furuichi K (March 2003). "Molecular identification of nicotinic acid receptor". Biochemical and Biophysical Research Communications. 303 (1): 364–9. doi:10.1016/S0006-291X(03)00342-5. PMID   12646212.
  10. ↑ "HCA2 receptor". International Union of Basic and Clinical Pharmacology. Retrieved 24 March 2016.
  11. ↑ Cooke M, Di Cónsoli H, Maloberti P, Cornejo Maciel F (May 2013). "Expression and function of OXE receptor, an eicosanoid receptor, in steroidogenic cells". Molecular and Cellular Endocrinology. 371 (1-2): 71–8. doi:10.1016/j.mce.2012.11.003. PMID   23159987.
  12. ↑ Pike NB (December 2005). "Flushing out the role of GPR109A (HM74A) in the clinical efficacy of nicotinic acid". The Journal of Clinical Investigation. 115 (12): 3400–3. doi:10.1172/JCI27160. PMC   1297267  Lock-green.svg. PMID   16322787.
  13. ↑ Tunaru S, Kero J, Schaub A, Wufka C, Blaukat A, Pfeffer K, Offermanns S (March 2003). "PUMA-G and HM74 are receptors for nicotinic acid and mediate its anti-lipolytic effect". Nature Medicine. 9 (3): 352–5. doi:10.1038/nm824. PMID   12563315.
  14. ↑ Benyó Z, Gille A, Kero J, Csiky M, Suchánková MC, Nüsing RM, Moers A, Pfeffer K, Offermanns S (December 2005). "GPR109A (PUMA-G/HM74A) mediates nicotinic acid-induced flushing". The Journal of Clinical Investigation. 115 (12): 3634–40. doi:10.1172/JCI23626. PMC   1297235  Lock-green.svg. PMID   16322797.
  15. 1 2 Walters RW, Shukla AK, Kovacs JJ, Violin JD, DeWire SM, Lam CM, Chen JR, Muehlbauer MJ, Whalen EJ, Lefkowitz RJ (May 2009). "beta-Arrestin1 mediates nicotinic acid-induced flushing, but not its antilipolytic effect, in mice". The Journal of Clinical Investigation. 119 (5): 1312–21. doi:10.1172/JCI36806. PMC   2673863  Lock-green.svg. PMID   19349687.
  16. 1 2 3 Offermanns S, Schwaninger M (April 2015). "Nutritional or pharmacological activation of HCA(2) ameliorates neuroinflammation". Trends in Molecular Medicine. 21 (4): 245–55. doi:10.1016/j.molmed.2015.02.002. PMID   25766751. Neuroinflammatory cells express HCA2, a receptor for the endogenous neuroprotective ketone body β-hydroxybutyrate (BHB) as well as for the drugs dimethyl fumarate (DMF) and nicotinic acid, which have established efficacy in the treatment of MS and experimental stroke, respectively. This review summarizes the evidence that HCA2 is involved in the therapeutic effects of DMF, nicotinic acid, and ketone bodies in reducing neuroinflammation.
  17. ↑ Chai JT, Digby JE, Choudhury RP (May 2013). "GPR109A and vascular inflammation". Current Atherosclerosis Reports. 15 (5): 325. doi:10.1007/s11883-013-0325-9. PMC   3631117  Lock-green.svg. PMID   23526298. This interest is generated especially because of the continuing exploration of niacin's "pleiotropic" mechanisms of action and its potential in the "cross-talk" between metabolic and inflammatory pathways. As GPR109A's primary pharmacological ligand in clinical use, niacin has been used for over 50 years in the treatment of cardiovascular disease, mainly due to its favourable effects on plasma lipoproteins. However, it has become apparent that niacin also possesses lipoprotein-independent effects that influence inflammatory pathways mediated through GPR109A. In addition to its G-protein-mediated effects, recent evidence has emerged to support alternative GPR109A signalling via adaptive protein β-arrestins.
  18. ↑ Graff EC, Fang H, Wanders D, Judd RL (February 2016). "Anti-inflammatory effects of the hydroxycarboxylic acid receptor 2". Metabolism. 65 (2): 102–13. doi:10.1016/j.metabol.2015.10.001. PMID   26773933. HCA2 is highly expressed on immune cells, including macrophages, monocytes, neutrophils and dermal dendritic cells, among other cell types. ... Recent studies demonstrate that HCA2 mediates profound anti-inflammatory effects in a variety of tissues, indicating that HCA2 may be an important therapeutic target for treating inflammatory disease processes.
  19. 1 2 Wakade C, Chong R (December 2014). "A novel treatment target for Parkinson's disease". Journal of the Neurological Sciences. 347 (1-2): 34–8. doi:10.1016/j.jns.2014.10.024. PMID   25455298. GPR109A and its agonists are known to exert anti-inflammatory actions in the skin, gut and retina.
  20. ↑ Zhang Y, Schmidt RJ, Foxworthy P, Emkey R, Oler JK, Large TH, Wang H, Su EW, Mosior MK, Eacho PI, Cao G (August 2005). "Niacin mediates lipolysis in adipose tissue through its G-protein coupled receptor HM74A". Biochemical and Biophysical Research Communications. 334 (2): 729–32. doi:10.1016/j.bbrc.2005.06.141. PMID   16018973.
  21. ↑ Richman JG, Kanemitsu-Parks M, Gaidarov I, Cameron JS, Griffin P, Zheng H, Guerra NC, Cham L, Maciejewski-Lenoir D, Behan DP, Boatman D, Chen R, Skinner P, Ornelas P, Waters MG, Wright SD, Semple G, Connolly DT (June 2007). "Nicotinic acid receptor agonists differentially activate downstream effectors". The Journal of Biological Chemistry. 282 (25): 18028–36. doi:10.1074/jbc.M701866200. PMID   17452318.
  22. ↑ Tang Y, Zhou L, Gunnet JW, Wines PG, Cryan EV, Demarest KT (June 2006). "Enhancement of arachidonic acid signaling pathway by nicotinic acid receptor HM74A". Biochemical and Biophysical Research Communications. 345 (1): 29–37. doi:10.1016/j.bbrc.2006.04.051. PMID   16674924.
  23. ↑ Kasubuchi M, Hasegawa S, Hiramatsu T, Ichimura A, Kimura I (April 2015). "Dietary gut microbial metabolites, short-chain fatty acids, and host metabolic regulation". Nutrients. 7 (4): 2839–49. doi:10.3390/nu7042839. PMC   4425176  Lock-green.svg. PMID   25875123. Short-chain fatty acids (SCFAs) such as acetate, butyrate, and propionate, which are produced by gut microbial fermentation of dietary fiber, are recognized as essential host energy sources and act as signal transduction molecules via G-protein coupled receptors (FFAR2, FFAR3, OLFR78, GPR109A) and as epigenetic regulators of gene expression by the inhibition of histone deacetylase (HDAC). Recent evidence suggests that dietary fiber and the gut microbial-derived SCFAs exert multiple beneficial effects on the host energy metabolism not only by improving the intestinal environment, but also by directly affecting various host peripheral tissues.
  24. ↑ Hoeppli RE, Wu D, Cook L, Levings MK (February 2015). "The environment of regulatory T cell biology: cytokines, metabolites, and the microbiome". Frontiers in Immunology. 6: 61. doi:10.3389/fimmu.2015.00061. PMC   4332351  Lock-green.svg. PMID   25741338. Specific species that have been recognized by their high levels of butyrate production include Faecalibacterium prausnitzii and the cluster IV and XIVa of genus Clostridium ... Administration of acetate, propionate, and butyrate in drinking water mimics the effect of Clostridium colonization in germ-free mice, resulting in an elevated Treg frequency in the colonic lamina propria and increased IL-10 production by these Tregs (180, 182). Of the three main SCFAs, butyrate has been found to be the most potent inducer of colonic Tregs. Mice fed a diet enriched in butyrylated starches have more colonic Tregs than those fed a diet containing propinylated or acetylated starches (181). Arpaia et al. tested an array of SCFAs purified from commensal bacteria and confirmed butyrate was the strongest SCFA-inducer of Tregs in vitro (180). Mechanistically, it has been proposed that butyrate, and possibly propionate, promote Tregs through inhibiting histone deacetylase (HDAC), causing increased acetylation of histone H3 in the Foxp3 CNS1 region, and thereby enhancing FOXP3 expression (180, 181). Short-chain fatty acids partially mediate their effects through G-protein coupled receptors (GPR), including GPR41, GPR43, and GPR109A. GPR41 and GPR43 are stimulated by all three major SCFAs (191), whereas GPR109A only interacts with butyrate (192).
    Figure 1: Microbial-derived molecules promote colonic Treg differentiation.

This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.