NAD+ - Revision history

Dmitry Dzhagarov: /* Counteracting NAD+ deficiency with NAD+ precursors */

2024-03-27T19:11:35Z

Counteracting NAD+ deficiency with NAD+ precursors

← Older revision		Revision as of 19:11, 27 March 2024
Line 53:		Line 53:

	=== Counteracting NAD<sup>+</sup> deficiency with NAD<sup>+</sup> precursors ===		=== Counteracting NAD<sup>+</sup> deficiency with NAD<sup>+</sup> precursors ===
	Boosting intracellular NAD<sup>+</sup> content has been suggested as a potential anti-aging strategy.<ref>Yang, T., Chan, N. Y. K., & Sauve, A. A. (2007). Syntheses of nicotinamide riboside and derivatives: effective agents for increasing nicotinamide adenine dinucleotide concentrations in mammalian cells. Journal of medicinal chemistry, 50(26), 6458-6461. PMID: 18052316 DOI: 10.1021/jm701001c</ref><ref>Bonkowski, M. S., & Sinclair, D. A. (2016). Slowing ageing by design: the rise of NAD+ and sirtuin-activating compounds. Nature reviews Molecular cell biology, 17(11), 679-690. PMID: 27552971 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5107309 5107309] DOI: 10.1038/nrm.2016.93</ref><ref>Wu, L. E., & Sinclair, D. A. (2016). Restoring stem cells—all you need is NAD+. Cell Research, 26(9), 971-972. PMID: 27339086 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5034109 5034109] DOI: 10.1038/cr.2016.80</ref><ref name="Riboside">Sharma, C., Donu, D., & Cen, Y. (2022). Emerging Role of Nicotinamide Riboside in Health and Diseases. Nutrients, 14(19), 3889. Nutrients 2022, 14(19), 3889; PMID: 36235542 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9571518 9571518] DOI:[https://doi.org/10.3390/nu14193889 10.3390/nu14193889] </ref> Despite limited conclusive evidence, supplements of NAD+ precursors, namely '''[[nicotinamide (NAM)]]''', '''[[niacin\|nicotinic acid (NA)]]'''<ref>Pirinen, E., Auranen, M., Khan, N. A., Brilhante, V., Urho, N., Pessia, A., ... & Suomalainen, A. (2020). Niacin cures systemic NAD+ deficiency and improves muscle performance in adult-onset mitochondrial myopathy. Cell metabolism, 31(6), 1078-1090. PMID: 32386566 DOI: 10.1016/j.cmet.2020.04.008</ref><ref>[https://youtu.be/7_CY7LrFPwU Niacin Increases NAD (Test Results)]</ref>, '''[[nicotinamide riboside (NR)]]''' and '''[[nicotinamide mononucleotide (NMN)]]''', aimed at increasing NAD+ levels are becoming increasingly popular.<ref>Palmer, R. D., Elnashar, M. M., & Vaccarezza, M. (2021). Precursor comparisons for the upregulation of nicotinamide adenine dinucleotide. Novel approaches for better aging. Aging Medicine, 4(3), 214-220. PMID: 34553119 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8444956 8444956] DOI: 10.1002/agm2.12170</ref> In addition, nutritional supplementation of [[trigonelline]] could serve as a NAD+ boosting strategy. <ref>Membrez, M., Migliavacca, E., Christen, S., Yaku, K., Trieu, J., Lee, A. K., ... & Feige, J. N. (2024). Trigonelline is an NAD+ precursor that improves muscle function during ageing and is reduced in human sarcopenia. Nature Metabolism, 6, 433–447 https://doi.org/10.1038/s42255-024-00997-x</ref>		Boosting intracellular NAD<sup>+</sup> content has been suggested as a potential anti-aging strategy.<ref>Yang, T., Chan, N. Y. K., & Sauve, A. A. (2007). Syntheses of nicotinamide riboside and derivatives: effective agents for increasing nicotinamide adenine dinucleotide concentrations in mammalian cells. Journal of medicinal chemistry, 50(26), 6458-6461. PMID: 18052316 DOI: 10.1021/jm701001c</ref><ref>Bonkowski, M. S., & Sinclair, D. A. (2016). Slowing ageing by design: the rise of NAD+ and sirtuin-activating compounds. Nature reviews Molecular cell biology, 17(11), 679-690. PMID: 27552971 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5107309 5107309] DOI: 10.1038/nrm.2016.93</ref><ref>Wu, L. E., & Sinclair, D. A. (2016). Restoring stem cells—all you need is NAD+. Cell Research, 26(9), 971-972. PMID: 27339086 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5034109 5034109] DOI: 10.1038/cr.2016.80</ref><ref name="Riboside">Sharma, C., Donu, D., & Cen, Y. (2022). Emerging Role of Nicotinamide Riboside in Health and Diseases. Nutrients, 14(19), 3889. Nutrients 2022, 14(19), 3889; PMID: 36235542 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9571518 9571518] DOI:[https://doi.org/10.3390/nu14193889 10.3390/nu14193889] </ref> Despite limited conclusive evidence, supplements of NAD+ precursors, namely '''[[nicotinamide (NAM)]]''', '''[[niacin\|nicotinic acid (NA)]]'''<ref>Pirinen, E., Auranen, M., Khan, N. A., Brilhante, V., Urho, N., Pessia, A., ... & Suomalainen, A. (2020). Niacin cures systemic NAD+ deficiency and improves muscle performance in adult-onset mitochondrial myopathy. Cell metabolism, 31(6), 1078-1090. PMID: 32386566 DOI: 10.1016/j.cmet.2020.04.008</ref><ref>[https://youtu.be/7_CY7LrFPwU Niacin Increases NAD (Test Results)]</ref>, '''[[nicotinamide riboside (NR)]]''' and '''[[nicotinamide mononucleotide (NMN)]]''', aimed at increasing NAD+ levels are becoming increasingly popular.<ref>Palmer, R. D., Elnashar, M. M., & Vaccarezza, M. (2021). Precursor comparisons for the upregulation of nicotinamide adenine dinucleotide. Novel approaches for better aging. Aging Medicine, 4(3), 214-220. PMID: 34553119 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8444956 8444956] DOI: 10.1002/agm2.12170</ref> In addition, nutritional supplementation of '''[[trigonelline]]''' could serve as a NAD+ boosting strategy. <ref>Membrez, M., Migliavacca, E., Christen, S., Yaku, K., Trieu, J., Lee, A. K., ... & Feige, J. N. (2024). Trigonelline is an NAD+ precursor that improves muscle function during ageing and is reduced in human sarcopenia. Nature Metabolism, 6, 433–447 https://doi.org/10.1038/s42255-024-00997-x</ref>

	While it is anticipated that NAD+ precursors can play beneficial protective roles in several conditions, they vary in their ability to promote NAD+ anabolism with differing adverse effects. Careful evaluation of the role of NAD+, whether friend or foe in ageing, should be considered.<ref name="Boosting"/>		While it is anticipated that NAD+ precursors can play beneficial protective roles in several conditions, they vary in their ability to promote NAD+ anabolism with differing adverse effects. Careful evaluation of the role of NAD+, whether friend or foe in ageing, should be considered.<ref name="Boosting"/>

Dmitry Dzhagarov: /* Counteracting NAD+ deficiency with NAD+ precursors */

2024-03-27T19:10:39Z

Counteracting NAD+ deficiency with NAD+ precursors

← Older revision		Revision as of 19:10, 27 March 2024
Line 53:		Line 53:

	=== Counteracting NAD<sup>+</sup> deficiency with NAD<sup>+</sup> precursors ===		=== Counteracting NAD<sup>+</sup> deficiency with NAD<sup>+</sup> precursors ===
	Boosting intracellular NAD<sup>+</sup> content has been suggested as a potential anti-aging strategy.<ref>Yang, T., Chan, N. Y. K., & Sauve, A. A. (2007). Syntheses of nicotinamide riboside and derivatives: effective agents for increasing nicotinamide adenine dinucleotide concentrations in mammalian cells. Journal of medicinal chemistry, 50(26), 6458-6461. PMID: 18052316 DOI: 10.1021/jm701001c</ref><ref>Bonkowski, M. S., & Sinclair, D. A. (2016). Slowing ageing by design: the rise of NAD+ and sirtuin-activating compounds. Nature reviews Molecular cell biology, 17(11), 679-690. PMID: 27552971 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5107309 5107309] DOI: 10.1038/nrm.2016.93</ref><ref>Wu, L. E., & Sinclair, D. A. (2016). Restoring stem cells—all you need is NAD+. Cell Research, 26(9), 971-972. PMID: 27339086 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5034109 5034109] DOI: 10.1038/cr.2016.80</ref><ref name="Riboside">Sharma, C., Donu, D., & Cen, Y. (2022). Emerging Role of Nicotinamide Riboside in Health and Diseases. Nutrients, 14(19), 3889. Nutrients 2022, 14(19), 3889; PMID: 36235542 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9571518 9571518] DOI:[https://doi.org/10.3390/nu14193889 10.3390/nu14193889] </ref> Despite limited conclusive evidence, supplements of NAD+ precursors, namely '''[[nicotinamide (NAM)]]''', '''[[niacin\|nicotinic acid (NA)]]'''<ref>Pirinen, E., Auranen, M., Khan, N. A., Brilhante, V., Urho, N., Pessia, A., ... & Suomalainen, A. (2020). Niacin cures systemic NAD+ deficiency and improves muscle performance in adult-onset mitochondrial myopathy. Cell metabolism, 31(6), 1078-1090. PMID: 32386566 DOI: 10.1016/j.cmet.2020.04.008</ref><ref>[https://youtu.be/7_CY7LrFPwU Niacin Increases NAD (Test Results)]</ref>, '''[[nicotinamide riboside (NR)]]''' and '''[[nicotinamide mononucleotide (NMN)]]''', aimed at increasing NAD+ levels are becoming increasingly popular.<ref>Palmer, R. D., Elnashar, M. M., & Vaccarezza, M. (2021). Precursor comparisons for the upregulation of nicotinamide adenine dinucleotide. Novel approaches for better aging. Aging Medicine, 4(3), 214-220. PMID: 34553119 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8444956 8444956] DOI: 10.1002/agm2.12170</ref>		Boosting intracellular NAD<sup>+</sup> content has been suggested as a potential anti-aging strategy.<ref>Yang, T., Chan, N. Y. K., & Sauve, A. A. (2007). Syntheses of nicotinamide riboside and derivatives: effective agents for increasing nicotinamide adenine dinucleotide concentrations in mammalian cells. Journal of medicinal chemistry, 50(26), 6458-6461. PMID: 18052316 DOI: 10.1021/jm701001c</ref><ref>Bonkowski, M. S., & Sinclair, D. A. (2016). Slowing ageing by design: the rise of NAD+ and sirtuin-activating compounds. Nature reviews Molecular cell biology, 17(11), 679-690. PMID: 27552971 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5107309 5107309] DOI: 10.1038/nrm.2016.93</ref><ref>Wu, L. E., & Sinclair, D. A. (2016). Restoring stem cells—all you need is NAD+. Cell Research, 26(9), 971-972. PMID: 27339086 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5034109 5034109] DOI: 10.1038/cr.2016.80</ref><ref name="Riboside">Sharma, C., Donu, D., & Cen, Y. (2022). Emerging Role of Nicotinamide Riboside in Health and Diseases. Nutrients, 14(19), 3889. Nutrients 2022, 14(19), 3889; PMID: 36235542 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9571518 9571518] DOI:[https://doi.org/10.3390/nu14193889 10.3390/nu14193889] </ref> Despite limited conclusive evidence, supplements of NAD+ precursors, namely '''[[nicotinamide (NAM)]]''', '''[[niacin\|nicotinic acid (NA)]]'''<ref>Pirinen, E., Auranen, M., Khan, N. A., Brilhante, V., Urho, N., Pessia, A., ... & Suomalainen, A. (2020). Niacin cures systemic NAD+ deficiency and improves muscle performance in adult-onset mitochondrial myopathy. Cell metabolism, 31(6), 1078-1090. PMID: 32386566 DOI: 10.1016/j.cmet.2020.04.008</ref><ref>[https://youtu.be/7_CY7LrFPwU Niacin Increases NAD (Test Results)]</ref>, '''[[nicotinamide riboside (NR)]]''' and '''[[nicotinamide mononucleotide (NMN)]]''', aimed at increasing NAD+ levels are becoming increasingly popular.<ref>Palmer, R. D., Elnashar, M. M., & Vaccarezza, M. (2021). Precursor comparisons for the upregulation of nicotinamide adenine dinucleotide. Novel approaches for better aging. Aging Medicine, 4(3), 214-220. PMID: 34553119 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8444956 8444956] DOI: 10.1002/agm2.12170</ref> In addition, nutritional supplementation of [[trigonelline]] could serve as a NAD+ boosting strategy. <ref>Membrez, M., Migliavacca, E., Christen, S., Yaku, K., Trieu, J., Lee, A. K., ... & Feige, J. N. (2024). Trigonelline is an NAD+ precursor that improves muscle function during ageing and is reduced in human sarcopenia. Nature Metabolism, 6, 433–447 https://doi.org/10.1038/s42255-024-00997-x</ref>

	While it is anticipated that NAD+ precursors can play beneficial protective roles in several conditions, they vary in their ability to promote NAD+ anabolism with differing adverse effects. Careful evaluation of the role of NAD+, whether friend or foe in ageing, should be considered.<ref name="Boosting"/>		While it is anticipated that NAD+ precursors can play beneficial protective roles in several conditions, they vary in their ability to promote NAD+ anabolism with differing adverse effects. Careful evaluation of the role of NAD+, whether friend or foe in ageing, should be considered.<ref name="Boosting"/>

Dmitry Dzhagarov: /* NAMPT */

2024-01-20T18:06:56Z

NAMPT

← Older revision		Revision as of 18:06, 20 January 2024
Line 45:		Line 45:

	NAMPT is the main bottleneck in NAD<sup>+</sup> biosynthetic pathway making it a regulator of the intracellular NAD pool. Thus, NAMPT influences the activity of NAD-dependent enzymes, thereby regulating cellular metabolism.<ref name="Rate"/>		NAMPT is the main bottleneck in NAD<sup>+</sup> biosynthetic pathway making it a regulator of the intracellular NAD pool. Thus, NAMPT influences the activity of NAD-dependent enzymes, thereby regulating cellular metabolism.<ref name="Rate"/>

			=== NAD-Capped RNAs ===
			Metabolites like NAD were found to function as 5′-cap structures of RNA. It is assumed that NAD-RNA defines a fundamental regulatory mechanism at the epitranscriptomic level.<ref>Ge, S., Wang, X., Wang, Y., Dong, M., Li, D., Niu, K., ... & Zhong, M. (2024). Hidden features of NAD-RNA epitranscriptome in Drosophila life cycle. Iscience, 27(1).</ref> Interestingly, despite the fact that NAD decreases with age, it was found that the number of NAD-capping events tended to increase in aged human subject.<ref name="RNA">Li, D., & Liu, N. (2023). Epitranscriptome analysis of NAD-capped RNA by spike-in-based normalization. bioRxiv, 2023-03. https://doi.org/10.1101/2023.03.23.534034</ref> A set of NAD-RNAs that are highly associated with age have been identified.<ref name="RNA"/> Specifically, select NAD-RNAs, such as those involved in protein folding (PDIA3), protein ubiquitination (SUMO1), and apoptosis (caspase 3 and 8), had increased capping with age, although the abundance at RNA transcript levels was not increased.<ref name="RNA"/> At the same time, NAD-capping genes linked to mRNA decay (UPF2), calmodulin binding (NRGN), and TGF-β signaling pathway (TGFB1) were decreased during aging.<ref name="RNA"/>

	== Ways of boosting NAD+ in aging ==		== Ways of boosting NAD+ in aging ==

Dmitry Dzhagarov at 16:38, 4 January 2024

2024-01-04T16:38:27Z

← Older revision		Revision as of 16:38, 4 January 2024
Line 2:		Line 2:
	Nicotinamide adenine dinucleotide ('''NAD<sup>+</sup>''') is a coenzyme found in all living cells. NAD is called a dinucleotide because it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an adenine nucleobase and the other a nicotinamide. It serves both as a critical '''coenzyme''' for enzymes that fuel reduction-oxidation reactions, carrying electrons from one reaction to another, and as a '''cosubstrate''' for other enzymes such as the '''[[sirtuins]]''', [[CD38]] and poly(adenosine diphosphate-ribose) polymerases ('''PARP''').		Nicotinamide adenine dinucleotide ('''NAD<sup>+</sup>''') is a coenzyme found in all living cells. NAD is called a dinucleotide because it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an adenine nucleobase and the other a nicotinamide. It serves both as a critical '''coenzyme''' for enzymes that fuel reduction-oxidation reactions, carrying electrons from one reaction to another, and as a '''cosubstrate''' for other enzymes such as the '''[[sirtuins]]''', [[CD38]] and poly(adenosine diphosphate-ribose) polymerases ('''PARP''').

	Cellular NAD<sup>+</sup> concentrations change during aging, and modulation of NAD<sup>+</sup> usage or production has been proposed to prolong both healthspan and lifespan in animal models.<ref>Lautrup, S.Hou, Y.Fang, E. F.Bohr, V. A. (2023). [~~https~~://perspectivesinmedicine.cshlp.org/content/~~early~~/~~2023~~/~~10/16/cshperspect.~~a041193.abstract Roles of NAD+ in Health and Aging]. Cold Spring ~~Harbor Laboratory Press~~, doi: 10.1101/cshperspect.a041193		Cellular NAD<sup>+</sup> concentrations change during aging, and modulation of NAD<sup>+</sup> usage or production has been proposed to prolong both healthspan and lifespan in animal models.<ref>Lautrup, S.Hou, Y.Fang, E. F.Bohr, V. A. (2023). [http://perspectivesinmedicine.cshlp.org/content/14/1/a041193.abstract Roles of NAD+ in Health and Aging]. Cold Spring Harb Perspect Med 2024; 14: a041320, doi: 10.1101/cshperspect.a041193 doi: 10.1101/cshperspect.a041165</ref><ref name="Central">Poljšak, B., Kovač, V., Špalj, S., & Milisav, I. (2023). The Central Role of the NAD+ Molecule in the Development of Aging and the Prevention of Chronic Age-Related Diseases: Strategies for NAD+ Modulation. International Journal of Molecular Sciences, 24(3), 2959. https://doi.org/10.3390/ijms24032959</ref><ref>Verdin, E. (2015). NAD⁺ in aging, metabolism, and neurodegeneration. Science (New York, NY), 350(6265), 1208-1213. PMID: 26785480 DOI: 10.1126/science.aac4854</ref><ref name="Verdin">Covarrubias, A. J., Perrone, R., Grozio, A., & Verdin, E. (2021). NAD+ metabolism and its roles in cellular processes during ageing. Nature Reviews Molecular Cell Biology, 22(2), 119-141. PMID: 33353981 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7963035 7963035] DOI: 10.1038/s41580-020-00313-x</ref><ref>Chini, C. C. S., Cordeiro, H. S., Tran, N. L. K., & Chini, E. N. (2023). NAD metabolism: Role in senescence regulation and aging. Aging Cell, e13920. PMID: 37424179 https://doi.org/10.1111/acel.13920 </ref>
	</ref><ref name="Central">Poljšak, B., Kovač, V., Špalj, S., & Milisav, I. (2023). The Central Role of the NAD+ Molecule in the Development of Aging and the Prevention of Chronic Age-Related Diseases: Strategies for NAD+ Modulation. International Journal of Molecular Sciences, 24(3), 2959. https://doi.org/10.3390/ijms24032959</ref><ref>Verdin, E. (2015). NAD⁺ in aging, metabolism, and neurodegeneration. Science (New York, NY), 350(6265), 1208-1213. PMID: 26785480 DOI: 10.1126/science.aac4854</ref><ref name="Verdin">Covarrubias, A. J., Perrone, R., Grozio, A., & Verdin, E. (2021). NAD+ metabolism and its roles in cellular processes during ageing. Nature Reviews Molecular Cell Biology, 22(2), 119-141. PMID: 33353981 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7963035 7963035] DOI: 10.1038/s41580-020-00313-x</ref><ref>Chini, C. C. S., Cordeiro, H. S., Tran, N. L. K., & Chini, E. N. (2023). NAD metabolism: Role in senescence regulation and aging. Aging Cell, e13920. PMID: 37424179 https://doi.org/10.1111/acel.13920 </ref>

	'''The latest study from the ITP (Interventions Testing Program), which tests for the reproducibility of the lifespan effects from a range of compounds, showed that NAD<sup>+</sup> supplementation had no effect in very old mice lifespan of either sex.'''<ref>Harrison, D. E., Strong, R., Reifsnyder, P., Kumar, N., Fernandez, E., Flurkey, K., ... & Miller, R. A. (2021). 17‐a‐estradiol late in life extends lifespan in aging UM‐HET3 male mice; nicotinamide riboside and three other drugs do not affect lifespan in either sex. ''Aging Cell'', ''20''(5), e13328.</ref> However, there is evidence that NAD<sup>+</sup> might have beneficial effects in health in rather old mice.<ref name="Central"/><ref name="Verdin" /> For example, a potent and selective CD38 inhibitor, '''78c''', has been shown to restore low NAD<sup>+</sup> levels in mouse models of aging, and thus protect against aging-induced health loss in aged male mice, resulting in an increase in lifespan (average by 17% and maximal by 14%).<ref name="78c">Peclat, T. R., Thompson, K. L., Warner, G. M., Chini, C. C., Tarragó, M. G., Mazdeh, D. Z., ... & Chini, E. N. (2022). CD38 inhibitor 78c increases mice lifespan and healthspan in a model of chronological aging. Aging Cell, e13589. PMID:35263032 doi:10.1111/acel.13589</ref>		'''The latest study from the ITP (Interventions Testing Program), which tests for the reproducibility of the lifespan effects from a range of compounds, showed that NAD<sup>+</sup> supplementation had no effect in very old mice lifespan of either sex.'''<ref>Harrison, D. E., Strong, R., Reifsnyder, P., Kumar, N., Fernandez, E., Flurkey, K., ... & Miller, R. A. (2021). 17‐a‐estradiol late in life extends lifespan in aging UM‐HET3 male mice; nicotinamide riboside and three other drugs do not affect lifespan in either sex. ''Aging Cell'', ''20''(5), e13328.</ref> However, there is evidence that NAD<sup>+</sup> might have beneficial effects in health in rather old mice.<ref name="Central"/><ref name="Verdin" /> For example, a potent and selective CD38 inhibitor, '''78c''', has been shown to restore low NAD<sup>+</sup> levels in mouse models of aging, and thus protect against aging-induced health loss in aged male mice, resulting in an increase in lifespan (average by 17% and maximal by 14%).<ref name="78c">Peclat, T. R., Thompson, K. L., Warner, G. M., Chini, C. C., Tarragó, M. G., Mazdeh, D. Z., ... & Chini, E. N. (2022). CD38 inhibitor 78c increases mice lifespan and healthspan in a model of chronological aging. Aging Cell, e13589. PMID:35263032 doi:10.1111/acel.13589</ref>

Dmitry Dzhagarov at 17:36, 18 October 2023

2023-10-18T17:36:23Z

← Older revision		Revision as of 17:36, 18 October 2023
Line 2:		Line 2:
	Nicotinamide adenine dinucleotide ('''NAD<sup>+</sup>''') is a coenzyme found in all living cells. NAD is called a dinucleotide because it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an adenine nucleobase and the other a nicotinamide. It serves both as a critical '''coenzyme''' for enzymes that fuel reduction-oxidation reactions, carrying electrons from one reaction to another, and as a '''cosubstrate''' for other enzymes such as the '''[[sirtuins]]''', [[CD38]] and poly(adenosine diphosphate-ribose) polymerases ('''PARP''').		Nicotinamide adenine dinucleotide ('''NAD<sup>+</sup>''') is a coenzyme found in all living cells. NAD is called a dinucleotide because it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an adenine nucleobase and the other a nicotinamide. It serves both as a critical '''coenzyme''' for enzymes that fuel reduction-oxidation reactions, carrying electrons from one reaction to another, and as a '''cosubstrate''' for other enzymes such as the '''[[sirtuins]]''', [[CD38]] and poly(adenosine diphosphate-ribose) polymerases ('''PARP''').

	Cellular NAD<sup>+</sup> concentrations change during aging, and modulation of NAD<sup>+</sup> usage or production has been proposed to prolong both healthspan and lifespan in animal models.<ref name="Central">Poljšak, B., Kovač, V., Špalj, S., & Milisav, I. (2023). The Central Role of the NAD+ Molecule in the Development of Aging and the Prevention of Chronic Age-Related Diseases: Strategies for NAD+ Modulation. International Journal of Molecular Sciences, 24(3), 2959. https://doi.org/10.3390/ijms24032959</ref><ref>Verdin, E. (2015). NAD⁺ in aging, metabolism, and neurodegeneration. Science (New York, NY), 350(6265), 1208-1213. PMID: 26785480 DOI: 10.1126/science.aac4854</ref><ref name="Verdin">Covarrubias, A. J., Perrone, R., Grozio, A., & Verdin, E. (2021). NAD+ metabolism and its roles in cellular processes during ageing. Nature Reviews Molecular Cell Biology, 22(2), 119-141. PMID: 33353981 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7963035 7963035] DOI: 10.1038/s41580-020-00313-x</ref><ref>Chini, C. C. S., Cordeiro, H. S., Tran, N. L. K., & Chini, E. N. (2023). NAD metabolism: Role in senescence regulation and aging. Aging Cell, e13920. PMID: 37424179 https://doi.org/10.1111/acel.13920 </ref>		Cellular NAD<sup>+</sup> concentrations change during aging, and modulation of NAD<sup>+</sup> usage or production has been proposed to prolong both healthspan and lifespan in animal models.<ref>Lautrup, S.Hou, Y.Fang, E. F.Bohr, V. A. (2023). [https://perspectivesinmedicine.cshlp.org/content/early/2023/10/16/cshperspect.a041193.abstract Roles of NAD+ in Health and Aging]. Cold Spring Harbor Laboratory Press, doi: 10.1101/cshperspect.a041193
			</ref><ref name="Central">Poljšak, B., Kovač, V., Špalj, S., & Milisav, I. (2023). The Central Role of the NAD+ Molecule in the Development of Aging and the Prevention of Chronic Age-Related Diseases: Strategies for NAD+ Modulation. International Journal of Molecular Sciences, 24(3), 2959. https://doi.org/10.3390/ijms24032959</ref><ref>Verdin, E. (2015). NAD⁺ in aging, metabolism, and neurodegeneration. Science (New York, NY), 350(6265), 1208-1213. PMID: 26785480 DOI: 10.1126/science.aac4854</ref><ref name="Verdin">Covarrubias, A. J., Perrone, R., Grozio, A., & Verdin, E. (2021). NAD+ metabolism and its roles in cellular processes during ageing. Nature Reviews Molecular Cell Biology, 22(2), 119-141. PMID: 33353981 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7963035 7963035] DOI: 10.1038/s41580-020-00313-x</ref><ref>Chini, C. C. S., Cordeiro, H. S., Tran, N. L. K., & Chini, E. N. (2023). NAD metabolism: Role in senescence regulation and aging. Aging Cell, e13920. PMID: 37424179 https://doi.org/10.1111/acel.13920 </ref>

	'''The latest study from the ITP (Interventions Testing Program), which tests for the reproducibility of the lifespan effects from a range of compounds, showed that NAD<sup>+</sup> supplementation had no effect in very old mice lifespan of either sex.'''<ref>Harrison, D. E., Strong, R., Reifsnyder, P., Kumar, N., Fernandez, E., Flurkey, K., ... & Miller, R. A. (2021). 17‐a‐estradiol late in life extends lifespan in aging UM‐HET3 male mice; nicotinamide riboside and three other drugs do not affect lifespan in either sex. ''Aging Cell'', ''20''(5), e13328.</ref> However, there is evidence that NAD<sup>+</sup> might have beneficial effects in health in rather old mice.<ref name="Central"/><ref name="Verdin" /> For example, a potent and selective CD38 inhibitor, '''78c''', has been shown to restore low NAD<sup>+</sup> levels in mouse models of aging, and thus protect against aging-induced health loss in aged male mice, resulting in an increase in lifespan (average by 17% and maximal by 14%).<ref name="78c">Peclat, T. R., Thompson, K. L., Warner, G. M., Chini, C. C., Tarragó, M. G., Mazdeh, D. Z., ... & Chini, E. N. (2022). CD38 inhibitor 78c increases mice lifespan and healthspan in a model of chronological aging. Aging Cell, e13589. PMID:35263032 doi:10.1111/acel.13589</ref>		'''The latest study from the ITP (Interventions Testing Program), which tests for the reproducibility of the lifespan effects from a range of compounds, showed that NAD<sup>+</sup> supplementation had no effect in very old mice lifespan of either sex.'''<ref>Harrison, D. E., Strong, R., Reifsnyder, P., Kumar, N., Fernandez, E., Flurkey, K., ... & Miller, R. A. (2021). 17‐a‐estradiol late in life extends lifespan in aging UM‐HET3 male mice; nicotinamide riboside and three other drugs do not affect lifespan in either sex. ''Aging Cell'', ''20''(5), e13328.</ref> However, there is evidence that NAD<sup>+</sup> might have beneficial effects in health in rather old mice.<ref name="Central"/><ref name="Verdin" /> For example, a potent and selective CD38 inhibitor, '''78c''', has been shown to restore low NAD<sup>+</sup> levels in mouse models of aging, and thus protect against aging-induced health loss in aged male mice, resulting in an increase in lifespan (average by 17% and maximal by 14%).<ref name="78c">Peclat, T. R., Thompson, K. L., Warner, G. M., Chini, C. C., Tarragó, M. G., Mazdeh, D. Z., ... & Chini, E. N. (2022). CD38 inhibitor 78c increases mice lifespan and healthspan in a model of chronological aging. Aging Cell, e13589. PMID:35263032 doi:10.1111/acel.13589</ref>

Dmitry Dzhagarov at 10:51, 27 July 2023

2023-07-27T10:51:24Z

← Older revision		Revision as of 10:51, 27 July 2023
Line 2:		Line 2:
	Nicotinamide adenine dinucleotide ('''NAD<sup>+</sup>''') is a coenzyme found in all living cells. NAD is called a dinucleotide because it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an adenine nucleobase and the other a nicotinamide. It serves both as a critical '''coenzyme''' for enzymes that fuel reduction-oxidation reactions, carrying electrons from one reaction to another, and as a '''cosubstrate''' for other enzymes such as the '''[[sirtuins]]''', [[CD38]] and poly(adenosine diphosphate-ribose) polymerases ('''PARP''').		Nicotinamide adenine dinucleotide ('''NAD<sup>+</sup>''') is a coenzyme found in all living cells. NAD is called a dinucleotide because it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an adenine nucleobase and the other a nicotinamide. It serves both as a critical '''coenzyme''' for enzymes that fuel reduction-oxidation reactions, carrying electrons from one reaction to another, and as a '''cosubstrate''' for other enzymes such as the '''[[sirtuins]]''', [[CD38]] and poly(adenosine diphosphate-ribose) polymerases ('''PARP''').

	Cellular NAD<sup>+</sup> concentrations change during aging, and modulation of NAD<sup>+</sup> usage or production has been proposed to prolong both healthspan and lifespan in animal models.<ref name="Central">Poljšak, B., Kovač, V., Špalj, S., & Milisav, I. (2023). The Central Role of the NAD+ Molecule in the Development of Aging and the Prevention of Chronic Age-Related Diseases: Strategies for NAD+ Modulation. International Journal of Molecular Sciences, 24(3), 2959. https://doi.org/10.3390/ijms24032959</ref><ref>Verdin, E. (2015). NAD⁺ in aging, metabolism, and neurodegeneration. Science (New York, NY), 350(6265), 1208-1213. PMID: 26785480 DOI: 10.1126/science.aac4854</ref><ref name="Verdin">Covarrubias, A. J., Perrone, R., Grozio, A., & Verdin, E. (2021). NAD+ metabolism and its roles in cellular processes during ageing. Nature Reviews Molecular Cell Biology, 22(2), 119-141. PMID: 33353981 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7963035 7963035] DOI: 10.1038/s41580-020-00313-x</ref>		Cellular NAD<sup>+</sup> concentrations change during aging, and modulation of NAD<sup>+</sup> usage or production has been proposed to prolong both healthspan and lifespan in animal models.<ref name="Central">Poljšak, B., Kovač, V., Špalj, S., & Milisav, I. (2023). The Central Role of the NAD+ Molecule in the Development of Aging and the Prevention of Chronic Age-Related Diseases: Strategies for NAD+ Modulation. International Journal of Molecular Sciences, 24(3), 2959. https://doi.org/10.3390/ijms24032959</ref><ref>Verdin, E. (2015). NAD⁺ in aging, metabolism, and neurodegeneration. Science (New York, NY), 350(6265), 1208-1213. PMID: 26785480 DOI: 10.1126/science.aac4854</ref><ref name="Verdin">Covarrubias, A. J., Perrone, R., Grozio, A., & Verdin, E. (2021). NAD+ metabolism and its roles in cellular processes during ageing. Nature Reviews Molecular Cell Biology, 22(2), 119-141. PMID: 33353981 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7963035 7963035] DOI: 10.1038/s41580-020-00313-x</ref><ref>Chini, C. C. S., Cordeiro, H. S., Tran, N. L. K., & Chini, E. N. (2023). NAD metabolism: Role in senescence regulation and aging. Aging Cell, e13920. PMID: 37424179 https://doi.org/10.1111/acel.13920 </ref>

	'''The latest study from the ITP (Interventions Testing Program), which tests for the reproducibility of the lifespan effects from a range of compounds, showed that NAD<sup>+</sup> supplementation had no effect in very old mice lifespan of either sex.'''<ref>Harrison, D. E., Strong, R., Reifsnyder, P., Kumar, N., Fernandez, E., Flurkey, K., ... & Miller, R. A. (2021). 17‐a‐estradiol late in life extends lifespan in aging UM‐HET3 male mice; nicotinamide riboside and three other drugs do not affect lifespan in either sex. ''Aging Cell'', ''20''(5), e13328.</ref> However, there is evidence that NAD<sup>+</sup> might have beneficial effects in health in rather old mice.<ref name="Central"/><ref name="Verdin" /> For example, a potent and selective CD38 inhibitor, '''78c''', has been shown to restore low NAD<sup>+</sup> levels in mouse models of aging, and thus protect against aging-induced health loss in aged male mice, resulting in an increase in lifespan (average by 17% and maximal by 14%).<ref name="78c">Peclat, T. R., Thompson, K. L., Warner, G. M., Chini, C. C., Tarragó, M. G., Mazdeh, D. Z., ... & Chini, E. N. (2022). CD38 inhibitor 78c increases mice lifespan and healthspan in a model of chronological aging. Aging Cell, e13589. PMID:35263032 doi:10.1111/acel.13589</ref>		'''The latest study from the ITP (Interventions Testing Program), which tests for the reproducibility of the lifespan effects from a range of compounds, showed that NAD<sup>+</sup> supplementation had no effect in very old mice lifespan of either sex.'''<ref>Harrison, D. E., Strong, R., Reifsnyder, P., Kumar, N., Fernandez, E., Flurkey, K., ... & Miller, R. A. (2021). 17‐a‐estradiol late in life extends lifespan in aging UM‐HET3 male mice; nicotinamide riboside and three other drugs do not affect lifespan in either sex. ''Aging Cell'', ''20''(5), e13328.</ref> However, there is evidence that NAD<sup>+</sup> might have beneficial effects in health in rather old mice.<ref name="Central"/><ref name="Verdin" /> For example, a potent and selective CD38 inhibitor, '''78c''', has been shown to restore low NAD<sup>+</sup> levels in mouse models of aging, and thus protect against aging-induced health loss in aged male mice, resulting in an increase in lifespan (average by 17% and maximal by 14%).<ref name="78c">Peclat, T. R., Thompson, K. L., Warner, G. M., Chini, C. C., Tarragó, M. G., Mazdeh, D. Z., ... & Chini, E. N. (2022). CD38 inhibitor 78c increases mice lifespan and healthspan in a model of chronological aging. Aging Cell, e13589. PMID:35263032 doi:10.1111/acel.13589</ref>

Dmitry Dzhagarov: /* Counteracting NAD+ deficiency with NAD+ precursors */

2023-07-27T10:18:31Z

Counteracting NAD+ deficiency with NAD+ precursors

← Older revision		Revision as of 10:18, 27 July 2023
Line 50:		Line 50:

	=== Counteracting NAD<sup>+</sup> deficiency with NAD<sup>+</sup> precursors ===		=== Counteracting NAD<sup>+</sup> deficiency with NAD<sup>+</sup> precursors ===
	Boosting intracellular NAD<sup>+</sup> content has been suggested as a potential anti-aging strategy.<ref>Yang, T., Chan, N. Y. K., & Sauve, A. A. (2007). Syntheses of nicotinamide riboside and derivatives: effective agents for increasing nicotinamide adenine dinucleotide concentrations in mammalian cells. Journal of medicinal chemistry, 50(26), 6458-6461. PMID: 18052316 DOI: 10.1021/jm701001c</ref><ref>Bonkowski, M. S., & Sinclair, D. A. (2016). Slowing ageing by design: the rise of NAD+ and sirtuin-activating compounds. Nature reviews Molecular cell biology, 17(11), 679-690. PMID: 27552971 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5107309 5107309] DOI: 10.1038/nrm.2016.93</ref><ref>Wu, L. E., & Sinclair, D. A. (2016). Restoring stem cells—all you need is NAD+. Cell Research, 26(9), 971-972. PMID: 27339086 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5034109 5034109] DOI: 10.1038/cr.2016.80</ref><ref name="Riboside">Sharma, C., Donu, D., & Cen, Y. (2022). Emerging Role of Nicotinamide Riboside in Health and Diseases. Nutrients, 14(19), 3889. Nutrients 2022, 14(19), 3889; PMID: 36235542 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9571518 9571518] DOI:[https://doi.org/10.3390/nu14193889 10.3390/nu14193889] </ref> Despite limited conclusive evidence, supplements of NAD+ precursors, namely '''[[nicotinamide (NAM)]]''', '''[[nicotinic acid (NA)]]''', '''[[nicotinamide riboside (NR)]]''' and '''[[nicotinamide mononucleotide (NMN)]]''', aimed at increasing NAD+ levels are becoming increasingly popular.<ref>Palmer, R. D., Elnashar, M. M., & Vaccarezza, M. (2021). Precursor comparisons for the upregulation of nicotinamide adenine dinucleotide. Novel approaches for better aging. Aging Medicine, 4(3), 214-220. PMID: 34553119 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8444956 8444956] DOI: 10.1002/agm2.12170</ref>		Boosting intracellular NAD<sup>+</sup> content has been suggested as a potential anti-aging strategy.<ref>Yang, T., Chan, N. Y. K., & Sauve, A. A. (2007). Syntheses of nicotinamide riboside and derivatives: effective agents for increasing nicotinamide adenine dinucleotide concentrations in mammalian cells. Journal of medicinal chemistry, 50(26), 6458-6461. PMID: 18052316 DOI: 10.1021/jm701001c</ref><ref>Bonkowski, M. S., & Sinclair, D. A. (2016). Slowing ageing by design: the rise of NAD+ and sirtuin-activating compounds. Nature reviews Molecular cell biology, 17(11), 679-690. PMID: 27552971 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5107309 5107309] DOI: 10.1038/nrm.2016.93</ref><ref>Wu, L. E., & Sinclair, D. A. (2016). Restoring stem cells—all you need is NAD+. Cell Research, 26(9), 971-972. PMID: 27339086 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5034109 5034109] DOI: 10.1038/cr.2016.80</ref><ref name="Riboside">Sharma, C., Donu, D., & Cen, Y. (2022). Emerging Role of Nicotinamide Riboside in Health and Diseases. Nutrients, 14(19), 3889. Nutrients 2022, 14(19), 3889; PMID: 36235542 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9571518 9571518] DOI:[https://doi.org/10.3390/nu14193889 10.3390/nu14193889] </ref> Despite limited conclusive evidence, supplements of NAD+ precursors, namely '''[[nicotinamide (NAM)]]''', '''[[niacin\|nicotinic acid (NA)]]'''<ref>Pirinen, E., Auranen, M., Khan, N. A., Brilhante, V., Urho, N., Pessia, A., ... & Suomalainen, A. (2020). Niacin cures systemic NAD+ deficiency and improves muscle performance in adult-onset mitochondrial myopathy. Cell metabolism, 31(6), 1078-1090. PMID: 32386566 DOI: 10.1016/j.cmet.2020.04.008</ref><ref>[https://youtu.be/7_CY7LrFPwU Niacin Increases NAD (Test Results)]</ref>, '''[[nicotinamide riboside (NR)]]''' and '''[[nicotinamide mononucleotide (NMN)]]''', aimed at increasing NAD+ levels are becoming increasingly popular.<ref>Palmer, R. D., Elnashar, M. M., & Vaccarezza, M. (2021). Precursor comparisons for the upregulation of nicotinamide adenine dinucleotide. Novel approaches for better aging. Aging Medicine, 4(3), 214-220. PMID: 34553119 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8444956 8444956] DOI: 10.1002/agm2.12170</ref>

	While it is anticipated that NAD+ precursors can play beneficial protective roles in several conditions, they vary in their ability to promote NAD+ anabolism with differing adverse effects. Careful evaluation of the role of NAD+, whether friend or foe in ageing, should be considered.<ref name="Boosting"/>		While it is anticipated that NAD+ precursors can play beneficial protective roles in several conditions, they vary in their ability to promote NAD+ anabolism with differing adverse effects. Careful evaluation of the role of NAD+, whether friend or foe in ageing, should be considered.<ref name="Boosting"/>

Dmitry Dzhagarov: /* GPR109A */

2023-07-23T18:44:28Z

GPR109A

← Older revision		Revision as of 18:44, 23 July 2023
Line 55:		Line 55:

	==== GPR109A ====		==== GPR109A ====
	GPR109A receptor also known as hydroxycarboxylic acid receptor 2 (HCAR2), niacin receptor 1 (NIACR1), HM74a, HM74b, and PUMA-G is located on chromosome 12 (Band 12q24.31) in humans.<ref>Zellner, C., Pullinger, C. R., Aouizerat, B. E., Frost, P. H., Kwok, P. Y., Malloy, M. J., & Kane, J. P. (2005). Variations in human HM74 (GPR109B) and HM74A (GPR109A) niacin receptors. Human mutation, 25(1), 18-21. PMID: 15580557 DOI: 10.1002/humu.20121</ref> The most notable agonist for GPR109A is niacin.<ref name="GPR109A">Taing, K., Chen, L., & Weng, H. R. (2023). Emerging roles of GPR109A in regulation of neuroinflammation in neurological diseases and pain. Neural Regeneration Research, 18(4), 763. PMID: 36204834 PMC9700108 DOI: 10.4103/1673-5374.354514</ref> The other endogenous agonists of GPR109A are Beta hydroxy butyrate (BHB) and butyrate, which are ketone bodies produced during ketosis. '''GPR109A is involved in the vascular inflammation pathway related to the antiatherosclerotic effect of niacin.'''<ref>Lukasova, M., Malaval, C., Gille, A., Kero, 1. J., & Offermanns, S. (2011). Nicotinic acid inhibits progression of atherosclerosis in mice through its receptor GPR109A expressed by immune cells. The Journal of clinical investigation, 121(3), 1163-1173. http://www.jci.org/articles/view/41651.</ref> GPR109A have long represented the molecular target for the anti-dyslipidemic actions of niacin and the endogenous ligand 3-hydroxy-butyric acid, being enriched on adipocytes.<ref>Yang, Y., Kang, H. J., Gao, R., Wang, J., Han, G. W., DiBerto, J. F., ... & Liu, Z. J. (2023). Structural insights into the human niacin receptor HCA2-Gi signalling complex. Nature Communications, 14(1), 1692. PMID: 36973264 PMCID: PMC10043007 DOI: 10.1038/s41467-023-37177-6</ref> '''Niacin (nicotinic acid) at high doses favorably modulates the human lipid profile by elevating high-density lipoprotein cholesterol (HDL-C) and decreasing low-density lipoprotein cholesterol (LDL-C) and lipoprotein a [Lp(a)]'''.<ref>Altschul, R., Hoffer, A., & Stephen, J. D. (1955). Influence of nicotinic acid on serum cholesterol in man. Archives of Biochemistry, 54, 558-559. </ref><ref>Lampsas, S., Xenou, M., Oikonomou, E., Pantelidis, P., Lysandrou, A., Sarantos, S., ... & Siasos, G. (2023). Lipoprotein (a) in Atherosclerotic Diseases: From Pathophysiology to Diagnosis and Treatment. Molecules, 28(3), 969. PMID: 36770634 PMC9918959 DOI: 10.3390/molecules28030969</ref><ref>Kühnast, S., Louwe, M. C., Heemskerk, M. M., Pieterman, E. J., van Klinken, J. B., van den Berg, S. A., ... & Jukema, J. W. (2013). Niacin reduces atherosclerosis development in APOE* 3Leiden. CETP mice mainly by reducing nonHDL-cholesterol. PloS one, 8(6), e66467. PMID: 23840481 PMCID: PMC3686722 DOI: 10.1371/journal.pone.0066467</ref> Nicotinamide riboside (NR) administration is a valid tool to boost NAD<sup>+</sup> levels in mammalian cells and tissues but without activating GPR109A and so without antiatherosclerotic effect.<ref>Cantó, C., Houtkooper, R. H., Pirinen, E., Youn, D. Y., Oosterveer, M. H., Cen, Y., ... & Auwerx, J. (2012). The NAD+ precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity. Cell metabolism, 15(6), 838-847. ~~PMID: 22682224 PMC3616313 DOI: 10.1016/j.cmet.2012.04.022</ref>~~ associated with a reduced risk of mortality.<ref>Canner, P. L., Berge, K. G., Wenger, N. K., Stamler, J., Friedman, L., Prineas, R. J., ... & Coronary Drug Project Research Group. (1986). Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin. Journal of the American College of Cardiology, 8(6), 1245-1255. </ref><ref>Tang, C., Eshak, E. S., Shirai, K., Tamakoshi, A., & Iso, H. (2023). Associations of dietary intakes of vitamins B1 and B3 with risk of mortality from CVD among Japanese men and women: the Japan Collaborative Cohort study. British Journal of Nutrition, 129(7), 1213-1220. PMID: 35466893 PMCID: PMC10011590 DOI: 10.1017/S0007114522001209</ref>		GPR109A receptor also known as hydroxycarboxylic acid receptor 2 (HCAR2), niacin receptor 1 (NIACR1), HM74a, HM74b, and PUMA-G is located on chromosome 12 (Band 12q24.31) in humans.<ref>Zellner, C., Pullinger, C. R., Aouizerat, B. E., Frost, P. H., Kwok, P. Y., Malloy, M. J., & Kane, J. P. (2005). Variations in human HM74 (GPR109B) and HM74A (GPR109A) niacin receptors. Human mutation, 25(1), 18-21. PMID: 15580557 DOI: 10.1002/humu.20121</ref> The most notable agonist for GPR109A is niacin.<ref name="GPR109A">Taing, K., Chen, L., & Weng, H. R. (2023). Emerging roles of GPR109A in regulation of neuroinflammation in neurological diseases and pain. Neural Regeneration Research, 18(4), 763. PMID: 36204834 PMC9700108 DOI: 10.4103/1673-5374.354514</ref> The other endogenous agonists of GPR109A are Beta hydroxy butyrate (BHB) and butyrate, which are ketone bodies produced during ketosis. '''GPR109A is involved in the vascular inflammation pathway related to the antiatherosclerotic effect of niacin.'''<ref>Lukasova, M., Malaval, C., Gille, A., Kero, 1. J., & Offermanns, S. (2011). Nicotinic acid inhibits progression of atherosclerosis in mice through its receptor GPR109A expressed by immune cells. The Journal of clinical investigation, 121(3), 1163-1173. http://www.jci.org/articles/view/41651.</ref> GPR109A have long represented the molecular target for the anti-dyslipidemic actions of niacin and the endogenous ligand 3-hydroxy-butyric acid, being enriched on adipocytes.<ref>Yang, Y., Kang, H. J., Gao, R., Wang, J., Han, G. W., DiBerto, J. F., ... & Liu, Z. J. (2023). Structural insights into the human niacin receptor HCA2-Gi signalling complex. Nature Communications, 14(1), 1692. PMID: 36973264 PMCID: PMC10043007 DOI: 10.1038/s41467-023-37177-6</ref> '''Niacin (nicotinic acid) at high doses favorably modulates the human lipid profile by elevating high-density lipoprotein cholesterol (HDL-C) and decreasing low-density lipoprotein cholesterol (LDL-C) and lipoprotein a [Lp(a)]'''<ref>Altschul, R., Hoffer, A., & Stephen, J. D. (1955). Influence of nicotinic acid on serum cholesterol in man. Archives of Biochemistry, 54, 558-559. </ref><ref>Lampsas, S., Xenou, M., Oikonomou, E., Pantelidis, P., Lysandrou, A., Sarantos, S., ... & Siasos, G. (2023). Lipoprotein (a) in Atherosclerotic Diseases: From Pathophysiology to Diagnosis and Treatment. Molecules, 28(3), 969. PMID: 36770634 PMC9918959 DOI: 10.3390/molecules28030969</ref><ref>Kühnast, S., Louwe, M. C., Heemskerk, M. M., Pieterman, E. J., van Klinken, J. B., van den Berg, S. A., ... & Jukema, J. W. (2013). Niacin reduces atherosclerosis development in APOE* 3Leiden. CETP mice mainly by reducing nonHDL-cholesterol. PloS one, 8(6), e66467. PMID: 23840481 PMCID: PMC3686722 DOI: 10.1371/journal.pone.0066467</ref> associated with a reduced risk of mortality.<ref>Canner, P. L., Berge, K. G., Wenger, N. K., Stamler, J., Friedman, L., Prineas, R. J., ... & Coronary Drug Project Research Group. (1986). Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin. Journal of the American College of Cardiology, 8(6), 1245-1255. </ref><ref>Tang, C., Eshak, E. S., Shirai, K., Tamakoshi, A., & Iso, H. (2023). Associations of dietary intakes of vitamins B1 and B3 with risk of mortality from CVD among Japanese men and women: the Japan Collaborative Cohort study. British Journal of Nutrition, 129(7), 1213-1220. PMID: 35466893 PMCID: PMC10011590 DOI: 10.1017/S0007114522001209</ref> Nicotinamide riboside (NR) administration is a valid tool to boost NAD<sup>+</sup> levels in mammalian cells and tissues but without activating GPR109A and so without antiatherosclerotic effect.<ref>Cantó, C., Houtkooper, R. H., Pirinen, E., Youn, D. Y., Oosterveer, M. H., Cen, Y., ... & Auwerx, J. (2012). The NAD+ precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity. Cell metabolism, 15(6), 838-847. PMID: 22682224 PMC3616313 DOI: 10.1016/j.cmet.2012.04.022</ref>
	It is interesting to note that besides niacin, some other small molecules are able to activate the GPR109A receptor, for example non-flushing<ref>Walters, R. W., Shukla, A. K., Kovacs, J. J., Violin, J. D., DeWire, S. M., Lam, C. M., ... & Lefkowitz, R. J. (2009). β-Arrestin1 mediates nicotinic acid–induced flushing, but not its antilipolytic effect, in mice. The Journal of clinical investigation, 119(5), 1312-1321. PMID: 19349687 PMC2673863 DOI: 10.1172/JCI36806</ref> '''MK-6892''',<ref>Shen, H. C., Ding, F. X., Raghavan, S., Deng, Q., Luell, S., Forrest, M. J., ... & Colletti, S. L. (2010). Discovery of a biaryl cyclohexene carboxylic acid (MK-6892): a potent and selective high affinity niacin receptor full agonist with reduced flushing profiles in animals as a preclinical candidate. Journal of medicinal chemistry, 53(6), 2666-2670. PMID: 20184326 DOI: 10.1021/jm100022r</ref><ref>Kim, H. Y., Jadhav, V. B., Jeong, D. Y., Park, W. K., Song, J. H., Lee, S., & Cho, H. (2015). Discovery of 4-(phenyl) thio-1 H-pyrazole derivatives as agonists of GPR109A, a high affinity niacin receptor. Archives of pharmacal research, 38, 1019-1032. PMID: 25599616 DOI: 10.1007/s12272-015-0560-4</ref>, not successful '''GSK256073''',<ref>Olson, E. J., Mahar, K. M., Haws, T. F., Fossler, M. J., Gao, F., de Gouville, A. C., ... & Lepore, J. J. (2019). A Randomized, Placebo‐Controlled Trial to Assess the Effects of 8 Weeks of Administration of GSK256073, a Selective GPR109A Agonist, on High‐Density Lipoprotein Cholesterol in Subjects With Dyslipidemia. Clinical Pharmacology in Drug Development, 8(7), 871-883. PMID: 31268250 DOI: 10.1002/cpdd.704</ref> and recently approved '''monomethyl fumarate (MMF, Bafiertam)'''.<ref>Yadav, M., Sarma, P., Ganguly, M., Mishra, S., Maharana, J., Zaidi, N., ... & Shukla, A. K. (2023). Structure-guided engineering of biased-agonism in the human niacin receptor via single amino acid substitution. bioRxiv, 2023-07. https://doi.org/10.1101/2023.07.03.547505</ref>		It is interesting to note that besides niacin, some other small molecules are able to activate the GPR109A receptor, for example non-flushing<ref>Walters, R. W., Shukla, A. K., Kovacs, J. J., Violin, J. D., DeWire, S. M., Lam, C. M., ... & Lefkowitz, R. J. (2009). β-Arrestin1 mediates nicotinic acid–induced flushing, but not its antilipolytic effect, in mice. The Journal of clinical investigation, 119(5), 1312-1321. PMID: 19349687 PMC2673863 DOI: 10.1172/JCI36806</ref> '''MK-6892''',<ref>Shen, H. C., Ding, F. X., Raghavan, S., Deng, Q., Luell, S., Forrest, M. J., ... & Colletti, S. L. (2010). Discovery of a biaryl cyclohexene carboxylic acid (MK-6892): a potent and selective high affinity niacin receptor full agonist with reduced flushing profiles in animals as a preclinical candidate. Journal of medicinal chemistry, 53(6), 2666-2670. PMID: 20184326 DOI: 10.1021/jm100022r</ref><ref>Kim, H. Y., Jadhav, V. B., Jeong, D. Y., Park, W. K., Song, J. H., Lee, S., & Cho, H. (2015). Discovery of 4-(phenyl) thio-1 H-pyrazole derivatives as agonists of GPR109A, a high affinity niacin receptor. Archives of pharmacal research, 38, 1019-1032. PMID: 25599616 DOI: 10.1007/s12272-015-0560-4</ref>, not successful '''GSK256073''',<ref>Olson, E. J., Mahar, K. M., Haws, T. F., Fossler, M. J., Gao, F., de Gouville, A. C., ... & Lepore, J. J. (2019). A Randomized, Placebo‐Controlled Trial to Assess the Effects of 8 Weeks of Administration of GSK256073, a Selective GPR109A Agonist, on High‐Density Lipoprotein Cholesterol in Subjects With Dyslipidemia. Clinical Pharmacology in Drug Development, 8(7), 871-883. PMID: 31268250 DOI: 10.1002/cpdd.704</ref> and recently approved '''monomethyl fumarate (MMF, Bafiertam)'''.<ref>Yadav, M., Sarma, P., Ganguly, M., Mishra, S., Maharana, J., Zaidi, N., ... & Shukla, A. K. (2023). Structure-guided engineering of biased-agonism in the human niacin receptor via single amino acid substitution. bioRxiv, 2023-07. https://doi.org/10.1101/2023.07.03.547505</ref>

Dmitry Dzhagarov: /* GPR109A */

2023-07-23T18:41:23Z

GPR109A

← Older revision		Revision as of 18:41, 23 July 2023
Line 55:		Line 55:

	==== GPR109A ====		==== GPR109A ====
	GPR109A receptor also known as hydroxycarboxylic acid receptor 2 (HCAR2), niacin receptor 1 (NIACR1), HM74a, HM74b, and PUMA-G is located on chromosome 12 (Band 12q24.31) in humans.<ref>Zellner, C., Pullinger, C. R., Aouizerat, B. E., Frost, P. H., Kwok, P. Y., Malloy, M. J., & Kane, J. P. (2005). Variations in human HM74 (GPR109B) and HM74A (GPR109A) niacin receptors. Human mutation, 25(1), 18-21. PMID: 15580557 DOI: 10.1002/humu.20121</ref> The most notable agonist for GPR109A is niacin.<ref name="GPR109A">Taing, K., Chen, L., & Weng, H. R. (2023). Emerging roles of GPR109A in regulation of neuroinflammation in neurological diseases and pain. Neural Regeneration Research, 18(4), 763. PMID: 36204834 PMC9700108 DOI: 10.4103/1673-5374.354514</ref> The other endogenous agonists of GPR109A are Beta hydroxy butyrate (BHB) and butyrate, which are ketone bodies produced during ketosis. '''GPR109A is involved in the vascular inflammation pathway related to the antiatherosclerotic effect of niacin.'''<ref>Lukasova, M., Malaval, C., Gille, A., Kero, 1. J., & Offermanns, S. (2011). Nicotinic acid inhibits progression of atherosclerosis in mice through its receptor GPR109A expressed by immune cells. The Journal of clinical investigation, 121(3), 1163-1173. http://www.jci.org/articles/view/41651.</ref> GPR109A have long represented the molecular target for the anti-dyslipidemic actions of niacin and the endogenous ligand 3-hydroxy-butyric acid, being enriched on adipocytes.<ref>Yang, Y., Kang, H. J., Gao, R., Wang, J., Han, G. W., DiBerto, J. F., ... & Liu, Z. J. (2023). Structural insights into the human niacin receptor HCA2-Gi signalling complex. Nature Communications, 14(1), 1692. PMID: 36973264 PMCID: PMC10043007 DOI: 10.1038/s41467-023-37177-6</ref> '''Niacin (nicotinic acid) at high doses favorably modulates the human lipid profile by elevating high-density lipoprotein cholesterol (HDL-C) and decreasing low-density lipoprotein cholesterol (LDL-C) and lipoprotein a [Lp(a)]'''.<ref>Altschul, R., Hoffer, A., & Stephen, J. D. (1955). Influence of nicotinic acid on serum cholesterol in man. Archives of Biochemistry, 54, 558-559. </ref><ref>Lampsas, S., Xenou, M., Oikonomou, E., Pantelidis, P., Lysandrou, A., Sarantos, S., ... & Siasos, G. (2023). Lipoprotein (a) in Atherosclerotic Diseases: From Pathophysiology to Diagnosis and Treatment. Molecules, 28(3), 969. PMID: 36770634 PMC9918959 DOI: 10.3390/molecules28030969</ref> Nicotinamide riboside (NR) administration is a valid tool to boost NAD<sup>+</sup> levels in mammalian cells and tissues but without activating GPR109A and so without antiatherosclerotic effect.<ref>Cantó, C., Houtkooper, R. H., Pirinen, E., Youn, D. Y., Oosterveer, M. H., Cen, Y., ... & Auwerx, J. (2012). The NAD+ precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity. Cell metabolism, 15(6), 838-847. PMID: 22682224 PMC3616313 DOI: 10.1016/j.cmet.2012.04.022</ref>		GPR109A receptor also known as hydroxycarboxylic acid receptor 2 (HCAR2), niacin receptor 1 (NIACR1), HM74a, HM74b, and PUMA-G is located on chromosome 12 (Band 12q24.31) in humans.<ref>Zellner, C., Pullinger, C. R., Aouizerat, B. E., Frost, P. H., Kwok, P. Y., Malloy, M. J., & Kane, J. P. (2005). Variations in human HM74 (GPR109B) and HM74A (GPR109A) niacin receptors. Human mutation, 25(1), 18-21. PMID: 15580557 DOI: 10.1002/humu.20121</ref> The most notable agonist for GPR109A is niacin.<ref name="GPR109A">Taing, K., Chen, L., & Weng, H. R. (2023). Emerging roles of GPR109A in regulation of neuroinflammation in neurological diseases and pain. Neural Regeneration Research, 18(4), 763. PMID: 36204834 PMC9700108 DOI: 10.4103/1673-5374.354514</ref> The other endogenous agonists of GPR109A are Beta hydroxy butyrate (BHB) and butyrate, which are ketone bodies produced during ketosis. '''GPR109A is involved in the vascular inflammation pathway related to the antiatherosclerotic effect of niacin.'''<ref>Lukasova, M., Malaval, C., Gille, A., Kero, 1. J., & Offermanns, S. (2011). Nicotinic acid inhibits progression of atherosclerosis in mice through its receptor GPR109A expressed by immune cells. The Journal of clinical investigation, 121(3), 1163-1173. http://www.jci.org/articles/view/41651.</ref> GPR109A have long represented the molecular target for the anti-dyslipidemic actions of niacin and the endogenous ligand 3-hydroxy-butyric acid, being enriched on adipocytes.<ref>Yang, Y., Kang, H. J., Gao, R., Wang, J., Han, G. W., DiBerto, J. F., ... & Liu, Z. J. (2023). Structural insights into the human niacin receptor HCA2-Gi signalling complex. Nature Communications, 14(1), 1692. PMID: 36973264 PMCID: PMC10043007 DOI: 10.1038/s41467-023-37177-6</ref> '''Niacin (nicotinic acid) at high doses favorably modulates the human lipid profile by elevating high-density lipoprotein cholesterol (HDL-C) and decreasing low-density lipoprotein cholesterol (LDL-C) and lipoprotein a [Lp(a)]'''.<ref>Altschul, R., Hoffer, A., & Stephen, J. D. (1955). Influence of nicotinic acid on serum cholesterol in man. Archives of Biochemistry, 54, 558-559. </ref><ref>Lampsas, S., Xenou, M., Oikonomou, E., Pantelidis, P., Lysandrou, A., Sarantos, S., ... & Siasos, G. (2023). Lipoprotein (a) in Atherosclerotic Diseases: From Pathophysiology to Diagnosis and Treatment. Molecules, 28(3), 969. PMID: 36770634 PMC9918959 DOI: 10.3390/molecules28030969</ref><ref>Kühnast, S., Louwe, M. C., Heemskerk, M. M., Pieterman, E. J., van Klinken, J. B., van den Berg, S. A., ... & Jukema, J. W. (2013). Niacin reduces atherosclerosis development in APOE* 3Leiden. CETP mice mainly by reducing nonHDL-cholesterol. PloS one, 8(6), e66467. PMID: 23840481 PMCID: PMC3686722 DOI: 10.1371/journal.pone.0066467</ref> Nicotinamide riboside (NR) administration is a valid tool to boost NAD<sup>+</sup> levels in mammalian cells and tissues but without activating GPR109A and so without antiatherosclerotic effect.<ref>Cantó, C., Houtkooper, R. H., Pirinen, E., Youn, D. Y., Oosterveer, M. H., Cen, Y., ... & Auwerx, J. (2012). The NAD+ precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity. Cell metabolism, 15(6), 838-847. PMID: 22682224 PMC3616313 DOI: 10.1016/j.cmet.2012.04.022</ref> associated with a reduced risk of mortality.<ref>Canner, P. L., Berge, K. G., Wenger, N. K., Stamler, J., Friedman, L., Prineas, R. J., ... & Coronary Drug Project Research Group. (1986). Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin. Journal of the American College of Cardiology, 8(6), 1245-1255. </ref><ref>Tang, C., Eshak, E. S., Shirai, K., Tamakoshi, A., & Iso, H. (2023). Associations of dietary intakes of vitamins B1 and B3 with risk of mortality from CVD among Japanese men and women: the Japan Collaborative Cohort study. British Journal of Nutrition, 129(7), 1213-1220. PMID: 35466893 PMCID: PMC10011590 DOI: 10.1017/S0007114522001209</ref>
	It is interesting to note that besides niacin, some other small molecules are able to activate the GPR109A receptor, for example non-flushing<ref>Walters, R. W., Shukla, A. K., Kovacs, J. J., Violin, J. D., DeWire, S. M., Lam, C. M., ... & Lefkowitz, R. J. (2009). β-Arrestin1 mediates nicotinic acid–induced flushing, but not its antilipolytic effect, in mice. The Journal of clinical investigation, 119(5), 1312-1321. PMID: 19349687 PMC2673863 DOI: 10.1172/JCI36806</ref> '''MK-6892''',<ref>Shen, H. C., Ding, F. X., Raghavan, S., Deng, Q., Luell, S., Forrest, M. J., ... & Colletti, S. L. (2010). Discovery of a biaryl cyclohexene carboxylic acid (MK-6892): a potent and selective high affinity niacin receptor full agonist with reduced flushing profiles in animals as a preclinical candidate. Journal of medicinal chemistry, 53(6), 2666-2670. PMID: 20184326 DOI: 10.1021/jm100022r</ref><ref>Kim, H. Y., Jadhav, V. B., Jeong, D. Y., Park, W. K., Song, J. H., Lee, S., & Cho, H. (2015). Discovery of 4-(phenyl) thio-1 H-pyrazole derivatives as agonists of GPR109A, a high affinity niacin receptor. Archives of pharmacal research, 38, 1019-1032. PMID: 25599616 DOI: 10.1007/s12272-015-0560-4</ref>, not successful '''GSK256073''',<ref>Olson, E. J., Mahar, K. M., Haws, T. F., Fossler, M. J., Gao, F., de Gouville, A. C., ... & Lepore, J. J. (2019). A Randomized, Placebo‐Controlled Trial to Assess the Effects of 8 Weeks of Administration of GSK256073, a Selective GPR109A Agonist, on High‐Density Lipoprotein Cholesterol in Subjects With Dyslipidemia. Clinical Pharmacology in Drug Development, 8(7), 871-883. PMID: 31268250 DOI: 10.1002/cpdd.704</ref> and recently approved '''monomethyl fumarate (MMF, Bafiertam)'''.<ref>Yadav, M., Sarma, P., Ganguly, M., Mishra, S., Maharana, J., Zaidi, N., ... & Shukla, A. K. (2023). Structure-guided engineering of biased-agonism in the human niacin receptor via single amino acid substitution. bioRxiv, 2023-07. https://doi.org/10.1101/2023.07.03.547505</ref>		It is interesting to note that besides niacin, some other small molecules are able to activate the GPR109A receptor, for example non-flushing<ref>Walters, R. W., Shukla, A. K., Kovacs, J. J., Violin, J. D., DeWire, S. M., Lam, C. M., ... & Lefkowitz, R. J. (2009). β-Arrestin1 mediates nicotinic acid–induced flushing, but not its antilipolytic effect, in mice. The Journal of clinical investigation, 119(5), 1312-1321. PMID: 19349687 PMC2673863 DOI: 10.1172/JCI36806</ref> '''MK-6892''',<ref>Shen, H. C., Ding, F. X., Raghavan, S., Deng, Q., Luell, S., Forrest, M. J., ... & Colletti, S. L. (2010). Discovery of a biaryl cyclohexene carboxylic acid (MK-6892): a potent and selective high affinity niacin receptor full agonist with reduced flushing profiles in animals as a preclinical candidate. Journal of medicinal chemistry, 53(6), 2666-2670. PMID: 20184326 DOI: 10.1021/jm100022r</ref><ref>Kim, H. Y., Jadhav, V. B., Jeong, D. Y., Park, W. K., Song, J. H., Lee, S., & Cho, H. (2015). Discovery of 4-(phenyl) thio-1 H-pyrazole derivatives as agonists of GPR109A, a high affinity niacin receptor. Archives of pharmacal research, 38, 1019-1032. PMID: 25599616 DOI: 10.1007/s12272-015-0560-4</ref>, not successful '''GSK256073''',<ref>Olson, E. J., Mahar, K. M., Haws, T. F., Fossler, M. J., Gao, F., de Gouville, A. C., ... & Lepore, J. J. (2019). A Randomized, Placebo‐Controlled Trial to Assess the Effects of 8 Weeks of Administration of GSK256073, a Selective GPR109A Agonist, on High‐Density Lipoprotein Cholesterol in Subjects With Dyslipidemia. Clinical Pharmacology in Drug Development, 8(7), 871-883. PMID: 31268250 DOI: 10.1002/cpdd.704</ref> and recently approved '''monomethyl fumarate (MMF, Bafiertam)'''.<ref>Yadav, M., Sarma, P., Ganguly, M., Mishra, S., Maharana, J., Zaidi, N., ... & Shukla, A. K. (2023). Structure-guided engineering of biased-agonism in the human niacin receptor via single amino acid substitution. bioRxiv, 2023-07. https://doi.org/10.1101/2023.07.03.547505</ref>

Dmitry Dzhagarov: /* GPR109A */

2023-07-23T18:06:09Z

GPR109A

← Older revision		Revision as of 18:06, 23 July 2023
Line 56:		Line 56:
	==== GPR109A ====		==== GPR109A ====
	GPR109A receptor also known as hydroxycarboxylic acid receptor 2 (HCAR2), niacin receptor 1 (NIACR1), HM74a, HM74b, and PUMA-G is located on chromosome 12 (Band 12q24.31) in humans.<ref>Zellner, C., Pullinger, C. R., Aouizerat, B. E., Frost, P. H., Kwok, P. Y., Malloy, M. J., & Kane, J. P. (2005). Variations in human HM74 (GPR109B) and HM74A (GPR109A) niacin receptors. Human mutation, 25(1), 18-21. PMID: 15580557 DOI: 10.1002/humu.20121</ref> The most notable agonist for GPR109A is niacin.<ref name="GPR109A">Taing, K., Chen, L., & Weng, H. R. (2023). Emerging roles of GPR109A in regulation of neuroinflammation in neurological diseases and pain. Neural Regeneration Research, 18(4), 763. PMID: 36204834 PMC9700108 DOI: 10.4103/1673-5374.354514</ref> The other endogenous agonists of GPR109A are Beta hydroxy butyrate (BHB) and butyrate, which are ketone bodies produced during ketosis. '''GPR109A is involved in the vascular inflammation pathway related to the antiatherosclerotic effect of niacin.'''<ref>Lukasova, M., Malaval, C., Gille, A., Kero, 1. J., & Offermanns, S. (2011). Nicotinic acid inhibits progression of atherosclerosis in mice through its receptor GPR109A expressed by immune cells. The Journal of clinical investigation, 121(3), 1163-1173. http://www.jci.org/articles/view/41651.</ref> GPR109A have long represented the molecular target for the anti-dyslipidemic actions of niacin and the endogenous ligand 3-hydroxy-butyric acid, being enriched on adipocytes.<ref>Yang, Y., Kang, H. J., Gao, R., Wang, J., Han, G. W., DiBerto, J. F., ... & Liu, Z. J. (2023). Structural insights into the human niacin receptor HCA2-Gi signalling complex. Nature Communications, 14(1), 1692. PMID: 36973264 PMCID: PMC10043007 DOI: 10.1038/s41467-023-37177-6</ref> '''Niacin (nicotinic acid) at high doses favorably modulates the human lipid profile by elevating high-density lipoprotein cholesterol (HDL-C) and decreasing low-density lipoprotein cholesterol (LDL-C) and lipoprotein a [Lp(a)]'''.<ref>Altschul, R., Hoffer, A., & Stephen, J. D. (1955). Influence of nicotinic acid on serum cholesterol in man. Archives of Biochemistry, 54, 558-559. </ref><ref>Lampsas, S., Xenou, M., Oikonomou, E., Pantelidis, P., Lysandrou, A., Sarantos, S., ... & Siasos, G. (2023). Lipoprotein (a) in Atherosclerotic Diseases: From Pathophysiology to Diagnosis and Treatment. Molecules, 28(3), 969. PMID: 36770634 PMC9918959 DOI: 10.3390/molecules28030969</ref> Nicotinamide riboside (NR) administration is a valid tool to boost NAD<sup>+</sup> levels in mammalian cells and tissues but without activating GPR109A and so without antiatherosclerotic effect.<ref>Cantó, C., Houtkooper, R. H., Pirinen, E., Youn, D. Y., Oosterveer, M. H., Cen, Y., ... & Auwerx, J. (2012). The NAD+ precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity. Cell metabolism, 15(6), 838-847. PMID: 22682224 PMC3616313 DOI: 10.1016/j.cmet.2012.04.022</ref>		GPR109A receptor also known as hydroxycarboxylic acid receptor 2 (HCAR2), niacin receptor 1 (NIACR1), HM74a, HM74b, and PUMA-G is located on chromosome 12 (Band 12q24.31) in humans.<ref>Zellner, C., Pullinger, C. R., Aouizerat, B. E., Frost, P. H., Kwok, P. Y., Malloy, M. J., & Kane, J. P. (2005). Variations in human HM74 (GPR109B) and HM74A (GPR109A) niacin receptors. Human mutation, 25(1), 18-21. PMID: 15580557 DOI: 10.1002/humu.20121</ref> The most notable agonist for GPR109A is niacin.<ref name="GPR109A">Taing, K., Chen, L., & Weng, H. R. (2023). Emerging roles of GPR109A in regulation of neuroinflammation in neurological diseases and pain. Neural Regeneration Research, 18(4), 763. PMID: 36204834 PMC9700108 DOI: 10.4103/1673-5374.354514</ref> The other endogenous agonists of GPR109A are Beta hydroxy butyrate (BHB) and butyrate, which are ketone bodies produced during ketosis. '''GPR109A is involved in the vascular inflammation pathway related to the antiatherosclerotic effect of niacin.'''<ref>Lukasova, M., Malaval, C., Gille, A., Kero, 1. J., & Offermanns, S. (2011). Nicotinic acid inhibits progression of atherosclerosis in mice through its receptor GPR109A expressed by immune cells. The Journal of clinical investigation, 121(3), 1163-1173. http://www.jci.org/articles/view/41651.</ref> GPR109A have long represented the molecular target for the anti-dyslipidemic actions of niacin and the endogenous ligand 3-hydroxy-butyric acid, being enriched on adipocytes.<ref>Yang, Y., Kang, H. J., Gao, R., Wang, J., Han, G. W., DiBerto, J. F., ... & Liu, Z. J. (2023). Structural insights into the human niacin receptor HCA2-Gi signalling complex. Nature Communications, 14(1), 1692. PMID: 36973264 PMCID: PMC10043007 DOI: 10.1038/s41467-023-37177-6</ref> '''Niacin (nicotinic acid) at high doses favorably modulates the human lipid profile by elevating high-density lipoprotein cholesterol (HDL-C) and decreasing low-density lipoprotein cholesterol (LDL-C) and lipoprotein a [Lp(a)]'''.<ref>Altschul, R., Hoffer, A., & Stephen, J. D. (1955). Influence of nicotinic acid on serum cholesterol in man. Archives of Biochemistry, 54, 558-559. </ref><ref>Lampsas, S., Xenou, M., Oikonomou, E., Pantelidis, P., Lysandrou, A., Sarantos, S., ... & Siasos, G. (2023). Lipoprotein (a) in Atherosclerotic Diseases: From Pathophysiology to Diagnosis and Treatment. Molecules, 28(3), 969. PMID: 36770634 PMC9918959 DOI: 10.3390/molecules28030969</ref> Nicotinamide riboside (NR) administration is a valid tool to boost NAD<sup>+</sup> levels in mammalian cells and tissues but without activating GPR109A and so without antiatherosclerotic effect.<ref>Cantó, C., Houtkooper, R. H., Pirinen, E., Youn, D. Y., Oosterveer, M. H., Cen, Y., ... & Auwerx, J. (2012). The NAD+ precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity. Cell metabolism, 15(6), 838-847. PMID: 22682224 PMC3616313 DOI: 10.1016/j.cmet.2012.04.022</ref>
	It is interesting to note that besides niacin, some other small molecules are able to activate the GPR109A receptor, for example non-flushing<ref>Walters, R. W., Shukla, A. K., Kovacs, J. J., Violin, J. D., DeWire, S. M., Lam, C. M., ... & Lefkowitz, R. J. (2009). β-Arrestin1 mediates nicotinic acid–induced flushing, but not its antilipolytic effect, in mice. The Journal of clinical investigation, 119(5), 1312-1321. PMID: 19349687 PMC2673863 DOI: 10.1172/JCI36806</ref> '''MK-6892''',<ref>Shen, H. C., Ding, F. X., Raghavan, S., Deng, Q., Luell, S., Forrest, M. J., ... & Colletti, S. L. (2010). Discovery of a biaryl cyclohexene carboxylic acid (MK-6892): a potent and selective high affinity niacin receptor full agonist with reduced flushing profiles in animals as a preclinical candidate. Journal of medicinal chemistry, 53(6), 2666-2670. PMID: 20184326 DOI: 10.1021/jm100022r</ref><ref>Kim, H. Y., Jadhav, V. B., Jeong, D. Y., Park, W. K., Song, J. H., Lee, S., & Cho, H. (2015). Discovery of 4-(phenyl) thio-1 H-pyrazole derivatives as agonists of GPR109A, a high affinity niacin receptor. Archives of pharmacal research, 38, 1019-1032. PMID: 25599616 DOI: 10.1007/s12272-015-0560-4</ref>, '''GSK256073''', and recently approved '''monomethyl fumarate (MMF, Bafiertam)''' <ref>Yadav, M., Sarma, P., Ganguly, M., Mishra, S., Maharana, J., Zaidi, N., ... & Shukla, A. K. (2023). Structure-guided engineering of biased-agonism in the human niacin receptor via single amino acid substitution. bioRxiv, 2023-07. https://doi.org/10.1101/2023.07.03.547505</ref> ~~however, no one has yet tested this molecules in clinical trials.~~		It is interesting to note that besides niacin, some other small molecules are able to activate the GPR109A receptor, for example non-flushing<ref>Walters, R. W., Shukla, A. K., Kovacs, J. J., Violin, J. D., DeWire, S. M., Lam, C. M., ... & Lefkowitz, R. J. (2009). β-Arrestin1 mediates nicotinic acid–induced flushing, but not its antilipolytic effect, in mice. The Journal of clinical investigation, 119(5), 1312-1321. PMID: 19349687 PMC2673863 DOI: 10.1172/JCI36806</ref> '''MK-6892''',<ref>Shen, H. C., Ding, F. X., Raghavan, S., Deng, Q., Luell, S., Forrest, M. J., ... & Colletti, S. L. (2010). Discovery of a biaryl cyclohexene carboxylic acid (MK-6892): a potent and selective high affinity niacin receptor full agonist with reduced flushing profiles in animals as a preclinical candidate. Journal of medicinal chemistry, 53(6), 2666-2670. PMID: 20184326 DOI: 10.1021/jm100022r</ref><ref>Kim, H. Y., Jadhav, V. B., Jeong, D. Y., Park, W. K., Song, J. H., Lee, S., & Cho, H. (2015). Discovery of 4-(phenyl) thio-1 H-pyrazole derivatives as agonists of GPR109A, a high affinity niacin receptor. Archives of pharmacal research, 38, 1019-1032. PMID: 25599616 DOI: 10.1007/s12272-015-0560-4</ref>, not successful '''GSK256073''',<ref>Olson, E. J., Mahar, K. M., Haws, T. F., Fossler, M. J., Gao, F., de Gouville, A. C., ... & Lepore, J. J. (2019). A Randomized, Placebo‐Controlled Trial to Assess the Effects of 8 Weeks of Administration of GSK256073, a Selective GPR109A Agonist, on High‐Density Lipoprotein Cholesterol in Subjects With Dyslipidemia. Clinical Pharmacology in Drug Development, 8(7), 871-883. PMID: 31268250 DOI: 10.1002/cpdd.704</ref> and recently approved '''monomethyl fumarate (MMF, Bafiertam)'''.<ref>Yadav, M., Sarma, P., Ganguly, M., Mishra, S., Maharana, J., Zaidi, N., ... & Shukla, A. K. (2023). Structure-guided engineering of biased-agonism in the human niacin receptor via single amino acid substitution. bioRxiv, 2023-07. https://doi.org/10.1101/2023.07.03.547505</ref>

	==== NAD<sup>+</sup> regulation by microbiome ====		==== NAD<sup>+</sup> regulation by microbiome ====