INDY (I’m Not Dead, Yet) - Revision history

Dmitry Dzhagarov: /* Inhibitors of SLC13a5 */

2024-01-09T19:11:32Z

Inhibitors of SLC13a5

← Older revision		Revision as of 19:11, 9 January 2024
Line 23:		Line 23:
	Obesity and type-2 diabetes are strong [[Risk factor\|risk factors]] for metabolically associated fatty liver disease ('''MAFLD'''), also known as Non-alcoholic fatty liver disease ('''NAFLD''').<ref>Stefan, N., & Cusi, K. (2022). A global view of the interplay between non-alcoholic fatty liver disease and diabetes. The Lancet Diabetes & Endocrinology. 10(4), 284-296 DOI:[https://doi.org/10.1016/S2213-8587(22)00003-1 10.1016/S2213-8587(22)00003-1]</ref> Increased mIndy mRNA expression in the liver is strongly associated with obesity, insulin resistance, and fatty liver disease in humans.<ref name="interleukin">von Loeffelholz, C., Lieske, S., Neuschäfer‐Rube, F., Willmes, D. M., Raschzok, N., Sauer, I. M., … & Birkenfeld, A. L. (2017). The human longevity gene homolog INDY and interleukin‐6 interact in hepatic lipid metabolism. Hepatology, 66(2), 616—630. PMID 28133767 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5519435 5519435] doi:10.1002/hep.29089</ref> So, one of approaches to treating human NAFLD, obesity and metabolic syndrome via influences on host metabolism and energy is targeting in the liver the activity of the SLC13a5 gene by inhibition with '''RNAi''',<ref>Brachs, S., Winkel, A. F., Tang, H., Birkenfeld, A. L., Brunner, B., Jahn-Hofmann, K., ... & Spranger, J. (2016). Inhibition of citrate cotransporter Slc13a5/mINDY by RNAi improves hepatic insulin sensitivity and prevents diet-induced non-alcoholic fatty liver disease in mice. Molecular metabolism, 5(11), 1072-1082. PMID: 27818933 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5081411 5081411] DOI: 10.1016/j.molmet.2016.08.004</ref> '''aptamers''',<ref name="aptamers"/> '''compound 2 (PF-06649298)''',<ref>EL-AGROUDY, N. E. R. M. E. E. N., ZAHN, G., HERRMANN, C., MINGRONE, G., ALVES, T. C., & BIRKENFELD, A. L. (2022). 839-P: Pharmacological Inhibition of Mammalian INDY Ameliorates Western Diet–Induced NASH in Mice: Possible Implication of FgfMPK Signaling. Diabetes, 71(Supplement_1). https://doi.org/10.2337/db22-839-P</ref> '''compound 4a''',<ref name="Potential">Willmes, D. M., Kurzbach, A., Henke, C., Schumann, T., Zahn, G., Heifetz, A., … & Birkenfeld, A. L. (2018). The longevity gene INDY (I’m Not Dead Yet) in metabolic control: Potential as pharmacological target. Pharmacology & therapeutics, 185, 1-11. PMID 28987323 Doi:[https://doi.org/10.1016/j.pharmthera.2017.10.003 10.1016/j.pharmthera.2017.10.003]</ref> '''BI01383298'''<ref name="species">Higuchi, K., Kopel, J. J., Sivaprakasam, S., Jaramillo-Martinez, V., Sutton, R. B., Urbatsch, I. L., & Ganapathy, V. (2020). Functional analysis of a species-specific inhibitor selective for human Na±coupled citrate transporter (NaCT/SLC13A5/mINDY). Biochemical Journal, 477(21), 4149-4165. PMID 33079129 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7657661 7657661] doi:10.1042/BCJ20200592</ref><ref name="interleukin"/>		Obesity and type-2 diabetes are strong [[Risk factor\|risk factors]] for metabolically associated fatty liver disease ('''MAFLD'''), also known as Non-alcoholic fatty liver disease ('''NAFLD''').<ref>Stefan, N., & Cusi, K. (2022). A global view of the interplay between non-alcoholic fatty liver disease and diabetes. The Lancet Diabetes & Endocrinology. 10(4), 284-296 DOI:[https://doi.org/10.1016/S2213-8587(22)00003-1 10.1016/S2213-8587(22)00003-1]</ref> Increased mIndy mRNA expression in the liver is strongly associated with obesity, insulin resistance, and fatty liver disease in humans.<ref name="interleukin">von Loeffelholz, C., Lieske, S., Neuschäfer‐Rube, F., Willmes, D. M., Raschzok, N., Sauer, I. M., … & Birkenfeld, A. L. (2017). The human longevity gene homolog INDY and interleukin‐6 interact in hepatic lipid metabolism. Hepatology, 66(2), 616—630. PMID 28133767 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5519435 5519435] doi:10.1002/hep.29089</ref> So, one of approaches to treating human NAFLD, obesity and metabolic syndrome via influences on host metabolism and energy is targeting in the liver the activity of the SLC13a5 gene by inhibition with '''RNAi''',<ref>Brachs, S., Winkel, A. F., Tang, H., Birkenfeld, A. L., Brunner, B., Jahn-Hofmann, K., ... & Spranger, J. (2016). Inhibition of citrate cotransporter Slc13a5/mINDY by RNAi improves hepatic insulin sensitivity and prevents diet-induced non-alcoholic fatty liver disease in mice. Molecular metabolism, 5(11), 1072-1082. PMID: 27818933 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5081411 5081411] DOI: 10.1016/j.molmet.2016.08.004</ref> '''aptamers''',<ref name="aptamers"/> '''compound 2 (PF-06649298)''',<ref>EL-AGROUDY, N. E. R. M. E. E. N., ZAHN, G., HERRMANN, C., MINGRONE, G., ALVES, T. C., & BIRKENFELD, A. L. (2022). 839-P: Pharmacological Inhibition of Mammalian INDY Ameliorates Western Diet–Induced NASH in Mice: Possible Implication of FgfMPK Signaling. Diabetes, 71(Supplement_1). https://doi.org/10.2337/db22-839-P</ref> '''compound 4a''',<ref name="Potential">Willmes, D. M., Kurzbach, A., Henke, C., Schumann, T., Zahn, G., Heifetz, A., … & Birkenfeld, A. L. (2018). The longevity gene INDY (I’m Not Dead Yet) in metabolic control: Potential as pharmacological target. Pharmacology & therapeutics, 185, 1-11. PMID 28987323 Doi:[https://doi.org/10.1016/j.pharmthera.2017.10.003 10.1016/j.pharmthera.2017.10.003]</ref> '''BI01383298'''<ref name="species">Higuchi, K., Kopel, J. J., Sivaprakasam, S., Jaramillo-Martinez, V., Sutton, R. B., Urbatsch, I. L., & Ganapathy, V. (2020). Functional analysis of a species-specific inhibitor selective for human Na±coupled citrate transporter (NaCT/SLC13A5/mINDY). Biochemical Journal, 477(21), 4149-4165. PMID 33079129 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7657661 7657661] doi:10.1042/BCJ20200592</ref><ref name="interleukin"/>
	A selective, human- and multi-species-active, non-competitive, non-substrate-like inhibitor of Slc13a5/mINDY activity, called '''ETG-5773''', has also been developed.<ref name="Inhibitor">Zahn, G., Willmes, D. M., El-Agroudy, N. N., Yarnold, C., Jarjes-Pike, R., Schaertl, S., ... & Birkenfeld, A. L. (2022). A Novel and Cross-Species Active Mammalian INDY (NaCT) Inhibitor Ameliorates Hepatic Steatosis in Mice with Diet-Induced Obesity. Metabolites, 12(8), 732.PMID: 36005604 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9413491 9413491] DOI: 10.3390/metabo12080732</ref> Diet-induced obesity mouse model treated with 15 mg/kg of compound ETG-5773 twice daily within a month had reduced body weight, fasting blood glucose, and insulin, and improved glucose tolerance. Mechanistic investigation in the seven-day study showed increased plasma '''β-hydroxybutyrate''' and '''activated''' '''hepatic AMPK''' (adenosine monophosphate-activated protein kinase), reflecting findings from Indy (−/−) knockout mice.<ref name="Inhibitor"/> So, by blocking the absorption of citrate, ETG-5773 is able to combat hepatic steatosis and fatty deposits, and therefore can be used in the future for the prevention and treatment of diet-induced obesity and non-alcoholic fatty liver disease due to metabolic disorders.<ref name="Inhibitor"/>		A selective, human- and multi-species-active, non-competitive, non-substrate-like inhibitor of Slc13a5/mINDY activity, called '''ETG-5773''', has also been developed.<ref name="Inhibitor">Zahn, G., Willmes, D. M., El-Agroudy, N. N., Yarnold, C., Jarjes-Pike, R., Schaertl, S., ... & Birkenfeld, A. L. (2022). A Novel and Cross-Species Active Mammalian INDY (NaCT) Inhibitor Ameliorates Hepatic Steatosis in Mice with Diet-Induced Obesity. Metabolites, 12(8), 732.PMID: 36005604 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9413491 9413491] DOI: 10.3390/metabo12080732</ref> Diet-induced obesity mouse model treated with 15 mg/kg of compound ETG-5773 twice daily within a month had reduced body weight, fasting blood glucose, and insulin, and improved glucose tolerance. Mechanistic investigation in the seven-day study showed increased plasma '''β-hydroxybutyrate''' and '''activated''' '''hepatic AMPK''' (adenosine monophosphate-activated protein kinase), reflecting findings from Indy (−/−) knockout mice.<ref name="Inhibitor"/> So, by blocking the absorption of citrate, ETG-5773 is able to combat hepatic steatosis and fatty deposits, and therefore can be used in the future for the prevention and treatment of diet-induced obesity and non-alcoholic fatty liver disease due to metabolic disorders.<ref name="Inhibitor"/>

			Pharmacological SLC13A5 inhibition could have utility in preventing or treating osteoporosis.<ref>Zahn, G., Baukmann, H. A., Wu, J., Jordan, J., Birkenfeld, A. L., Dirckx, N., & Schmidt, M. F. (2023). Targeting Longevity Gene SLC13A5: A Novel Approach to Prevent Age-Related Bone Fragility and Osteoporosis. Metabolites, 13(12), 1186. PMID: 38132868 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10744747/ PMC10744747] DOI: 10.3390/metabo13121186</ref>

	== See also ==		== See also ==

Dmitry Dzhagarov: /* Inhibitors of SLC13a5 */

2022-12-27T13:33:57Z

Inhibitors of SLC13a5

← Older revision		Revision as of 13:33, 27 December 2022
Line 21:		Line 21:
	Studies using '''antisense oligonucleotides''' to suppress mIndy in rats have demonstrated '''an improvement in insulin sensitivity''', which has been attributed to improved hepatic glucose production and insulin sensitivity.<ref name="aptamers">Pesta, D. H., Perry, R. J., Guebre-Egziabher, F., Zhang, D., Jurczak, M., Fischer-Rosinsky, A., … & Birkenfeld, A. L. (2015). Prevention of diet-induced hepatic steatosis and hepatic insulin resistance by second generation antisense oligonucleotides targeted to the longevity gene mIndy (Slc13a5). Aging (Albany NY), 7(12), 1086. PMID 26647160 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4712334 4712334] DOI:[https://doi.org/10.18632/aging.100854 10.18632/aging.100854]</ref>		Studies using '''antisense oligonucleotides''' to suppress mIndy in rats have demonstrated '''an improvement in insulin sensitivity''', which has been attributed to improved hepatic glucose production and insulin sensitivity.<ref name="aptamers">Pesta, D. H., Perry, R. J., Guebre-Egziabher, F., Zhang, D., Jurczak, M., Fischer-Rosinsky, A., … & Birkenfeld, A. L. (2015). Prevention of diet-induced hepatic steatosis and hepatic insulin resistance by second generation antisense oligonucleotides targeted to the longevity gene mIndy (Slc13a5). Aging (Albany NY), 7(12), 1086. PMID 26647160 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4712334 4712334] DOI:[https://doi.org/10.18632/aging.100854 10.18632/aging.100854]</ref>

	Obesity and type-2 diabetes are strong [[Risk factor\|risk factors]] for metabolically associated fatty liver disease ('''MAFLD'''), also known as Non-alcoholic fatty liver disease ('''NAFLD''').<ref>Stefan, N., & Cusi, K. (2022). A global view of the interplay between non-alcoholic fatty liver disease and diabetes. The Lancet Diabetes & Endocrinology. 10(4), 284-296 DOI:[https://doi.org/10.1016/S2213-8587(22)00003-1 10.1016/S2213-8587(22)00003-1]</ref> Increased mIndy mRNA expression in the liver is strongly associated with obesity, insulin resistance, and fatty liver disease in humans.<ref name="interleukin">von Loeffelholz, C., Lieske, S., Neuschäfer‐Rube, F., Willmes, D. M., Raschzok, N., Sauer, I. M., … & Birkenfeld, A. L. (2017). The human longevity gene homolog INDY and interleukin‐6 interact in hepatic lipid metabolism. Hepatology, 66(2), 616—630. PMID 28133767 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5519435 5519435] doi:10.1002/hep.29089</ref> So, one of approaches to treating human NAFLD, obesity and metabolic syndrome via influences on host metabolism and energy is targeting in the liver the activity of the SLC13a5 gene by inhibition with '''RNAi''',<ref>Brachs, S., Winkel, A. F., Tang, H., Birkenfeld, A. L., Brunner, B., Jahn-Hofmann, K., ... & Spranger, J. (2016). Inhibition of citrate cotransporter Slc13a5/mINDY by RNAi improves hepatic insulin sensitivity and prevents diet-induced non-alcoholic fatty liver disease in mice. Molecular metabolism, 5(11), 1072-1082. PMID: 27818933 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5081411 5081411] DOI: 10.1016/j.molmet.2016.08.004</ref> '''aptamers''',<ref name="aptamers"/> '''compound 2 (PF-06649298)''', '''compound 4a''',<ref name="Potential">Willmes, D. M., Kurzbach, A., Henke, C., Schumann, T., Zahn, G., Heifetz, A., … & Birkenfeld, A. L. (2018). The longevity gene INDY (I’m Not Dead Yet) in metabolic control: Potential as pharmacological target. Pharmacology & therapeutics, 185, 1-11. PMID 28987323 Doi:[https://doi.org/10.1016/j.pharmthera.2017.10.003 10.1016/j.pharmthera.2017.10.003]</ref> '''BI01383298'''<ref name="species">Higuchi, K., Kopel, J. J., Sivaprakasam, S., Jaramillo-Martinez, V., Sutton, R. B., Urbatsch, I. L., & Ganapathy, V. (2020). Functional analysis of a species-specific inhibitor selective for human Na±coupled citrate transporter (NaCT/SLC13A5/mINDY). Biochemical Journal, 477(21), 4149-4165. PMID 33079129 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7657661 7657661] doi:10.1042/BCJ20200592</ref><ref name="interleukin"/>		Obesity and type-2 diabetes are strong [[Risk factor\|risk factors]] for metabolically associated fatty liver disease ('''MAFLD'''), also known as Non-alcoholic fatty liver disease ('''NAFLD''').<ref>Stefan, N., & Cusi, K. (2022). A global view of the interplay between non-alcoholic fatty liver disease and diabetes. The Lancet Diabetes & Endocrinology. 10(4), 284-296 DOI:[https://doi.org/10.1016/S2213-8587(22)00003-1 10.1016/S2213-8587(22)00003-1]</ref> Increased mIndy mRNA expression in the liver is strongly associated with obesity, insulin resistance, and fatty liver disease in humans.<ref name="interleukin">von Loeffelholz, C., Lieske, S., Neuschäfer‐Rube, F., Willmes, D. M., Raschzok, N., Sauer, I. M., … & Birkenfeld, A. L. (2017). The human longevity gene homolog INDY and interleukin‐6 interact in hepatic lipid metabolism. Hepatology, 66(2), 616—630. PMID 28133767 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5519435 5519435] doi:10.1002/hep.29089</ref> So, one of approaches to treating human NAFLD, obesity and metabolic syndrome via influences on host metabolism and energy is targeting in the liver the activity of the SLC13a5 gene by inhibition with '''RNAi''',<ref>Brachs, S., Winkel, A. F., Tang, H., Birkenfeld, A. L., Brunner, B., Jahn-Hofmann, K., ... & Spranger, J. (2016). Inhibition of citrate cotransporter Slc13a5/mINDY by RNAi improves hepatic insulin sensitivity and prevents diet-induced non-alcoholic fatty liver disease in mice. Molecular metabolism, 5(11), 1072-1082. PMID: 27818933 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5081411 5081411] DOI: 10.1016/j.molmet.2016.08.004</ref> '''aptamers''',<ref name="aptamers"/> '''compound 2 (PF-06649298)''',<ref>EL-AGROUDY, N. E. R. M. E. E. N., ZAHN, G., HERRMANN, C., MINGRONE, G., ALVES, T. C., & BIRKENFELD, A. L. (2022). 839-P: Pharmacological Inhibition of Mammalian INDY Ameliorates Western Diet–Induced NASH in Mice: Possible Implication of FgfMPK Signaling. Diabetes, 71(Supplement_1). https://doi.org/10.2337/db22-839-P</ref> '''compound 4a''',<ref name="Potential">Willmes, D. M., Kurzbach, A., Henke, C., Schumann, T., Zahn, G., Heifetz, A., … & Birkenfeld, A. L. (2018). The longevity gene INDY (I’m Not Dead Yet) in metabolic control: Potential as pharmacological target. Pharmacology & therapeutics, 185, 1-11. PMID 28987323 Doi:[https://doi.org/10.1016/j.pharmthera.2017.10.003 10.1016/j.pharmthera.2017.10.003]</ref> '''BI01383298'''<ref name="species">Higuchi, K., Kopel, J. J., Sivaprakasam, S., Jaramillo-Martinez, V., Sutton, R. B., Urbatsch, I. L., & Ganapathy, V. (2020). Functional analysis of a species-specific inhibitor selective for human Na±coupled citrate transporter (NaCT/SLC13A5/mINDY). Biochemical Journal, 477(21), 4149-4165. PMID 33079129 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7657661 7657661] doi:10.1042/BCJ20200592</ref><ref name="interleukin"/>
	A selective, human- and multi-species-active, non-competitive, non-substrate-like inhibitor of Slc13a5/mINDY activity, called '''ETG-5773''', has also been developed.<ref name="Inhibitor">Zahn, G., Willmes, D. M., El-Agroudy, N. N., Yarnold, C., Jarjes-Pike, R., Schaertl, S., ... & Birkenfeld, A. L. (2022). A Novel and Cross-Species Active Mammalian INDY (NaCT) Inhibitor Ameliorates Hepatic Steatosis in Mice with Diet-Induced Obesity. Metabolites, 12(8), 732.PMID: 36005604 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9413491 9413491] DOI: 10.3390/metabo12080732</ref> Diet-induced obesity mouse model treated with 15 mg/kg of compound ETG-5773 twice daily within a month had reduced body weight, fasting blood glucose, and insulin, and improved glucose tolerance. Mechanistic investigation in the seven-day study showed increased plasma '''β-hydroxybutyrate''' and '''activated''' '''hepatic AMPK''' (adenosine monophosphate-activated protein kinase), reflecting findings from Indy (−/−) knockout mice.<ref name="Inhibitor"/> So, by blocking the absorption of citrate, ETG-5773 is able to combat hepatic steatosis and fatty deposits, and therefore can be used in the future for the prevention and treatment of diet-induced obesity and non-alcoholic fatty liver disease due to metabolic disorders.<ref name="Inhibitor"/>		A selective, human- and multi-species-active, non-competitive, non-substrate-like inhibitor of Slc13a5/mINDY activity, called '''ETG-5773''', has also been developed.<ref name="Inhibitor">Zahn, G., Willmes, D. M., El-Agroudy, N. N., Yarnold, C., Jarjes-Pike, R., Schaertl, S., ... & Birkenfeld, A. L. (2022). A Novel and Cross-Species Active Mammalian INDY (NaCT) Inhibitor Ameliorates Hepatic Steatosis in Mice with Diet-Induced Obesity. Metabolites, 12(8), 732.PMID: 36005604 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9413491 9413491] DOI: 10.3390/metabo12080732</ref> Diet-induced obesity mouse model treated with 15 mg/kg of compound ETG-5773 twice daily within a month had reduced body weight, fasting blood glucose, and insulin, and improved glucose tolerance. Mechanistic investigation in the seven-day study showed increased plasma '''β-hydroxybutyrate''' and '''activated''' '''hepatic AMPK''' (adenosine monophosphate-activated protein kinase), reflecting findings from Indy (−/−) knockout mice.<ref name="Inhibitor"/> So, by blocking the absorption of citrate, ETG-5773 is able to combat hepatic steatosis and fatty deposits, and therefore can be used in the future for the prevention and treatment of diet-induced obesity and non-alcoholic fatty liver disease due to metabolic disorders.<ref name="Inhibitor"/>

Andrea: category change

2022-12-27T12:34:14Z

category change

← Older revision		Revision as of 12:34, 27 December 2022
Line 2:		Line 2:

	The molecular mechanism, by which the heterozygote advantage of Indy on longevity is mediated, involves modulation of Indy transcription<ref name="Rogina"/><ref name="calorie"/>		The molecular mechanism, by which the heterozygote advantage of Indy on longevity is mediated, involves modulation of Indy transcription<ref name="Rogina"/><ref name="calorie"/>


	=== Indy homologues ===		=== Indy homologues ===
	[[File:MINDY targeted interventions.jpg\|thumb\| mINDY targeted interventions to promote a healthier and longer life. According to Mishra et al. 2021<ref name="Mishra"> Mishra, D., Kannan, K., Meadows, K., Macro, J., Li, M., Frankel, S., & Rogina, B. (2021). INDY—From Flies to Worms, Mice, Rats, Non-Human Primates, and Humans. Frontiers in Aging, 73. Doi:[https://doi.org/10.3389/fragi.2021.782162 10.3389/fragi.2021.782162]</ref>]]		[[File:MINDY targeted interventions.jpg\|thumb\| mINDY targeted interventions to promote a healthier and longer life. According to Mishra et al. 2021<ref name="Mishra"> Mishra, D., Kannan, K., Meadows, K., Macro, J., Li, M., Frankel, S., & Rogina, B. (2021). INDY—From Flies to Worms, Mice, Rats, Non-Human Primates, and Humans. Frontiers in Aging, 73. Doi:[https://doi.org/10.3389/fragi.2021.782162 10.3389/fragi.2021.782162]</ref>]]
Line 23:		Line 21:
	Studies using '''antisense oligonucleotides''' to suppress mIndy in rats have demonstrated '''an improvement in insulin sensitivity''', which has been attributed to improved hepatic glucose production and insulin sensitivity.<ref name="aptamers">Pesta, D. H., Perry, R. J., Guebre-Egziabher, F., Zhang, D., Jurczak, M., Fischer-Rosinsky, A., … & Birkenfeld, A. L. (2015). Prevention of diet-induced hepatic steatosis and hepatic insulin resistance by second generation antisense oligonucleotides targeted to the longevity gene mIndy (Slc13a5). Aging (Albany NY), 7(12), 1086. PMID 26647160 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4712334 4712334] DOI:[https://doi.org/10.18632/aging.100854 10.18632/aging.100854]</ref>		Studies using '''antisense oligonucleotides''' to suppress mIndy in rats have demonstrated '''an improvement in insulin sensitivity''', which has been attributed to improved hepatic glucose production and insulin sensitivity.<ref name="aptamers">Pesta, D. H., Perry, R. J., Guebre-Egziabher, F., Zhang, D., Jurczak, M., Fischer-Rosinsky, A., … & Birkenfeld, A. L. (2015). Prevention of diet-induced hepatic steatosis and hepatic insulin resistance by second generation antisense oligonucleotides targeted to the longevity gene mIndy (Slc13a5). Aging (Albany NY), 7(12), 1086. PMID 26647160 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4712334 4712334] DOI:[https://doi.org/10.18632/aging.100854 10.18632/aging.100854]</ref>

	Obesity and type 2 diabetes are strong risk factors for metabolically associated fatty liver disease ('''MAFLD'''), also known as Non-alcoholic fatty liver disease ('''NAFLD''').<ref>Stefan, N., & Cusi, K. (2022). A global view of the interplay between non-alcoholic fatty liver disease and diabetes. The Lancet Diabetes & Endocrinology. 10(4), 284-296 DOI:[https://doi.org/10.1016/S2213-8587(22)00003-1 10.1016/S2213-8587(22)00003-1]</ref> Increased mIndy mRNA expression in the liver is strongly associated with obesity, insulin resistance, and fatty liver disease in humans.<ref name="interleukin">von Loeffelholz, C., Lieske, S., Neuschäfer‐Rube, F., Willmes, D. M., Raschzok, N., Sauer, I. M., … & Birkenfeld, A. L. (2017). The human longevity gene homolog INDY and interleukin‐6 interact in hepatic lipid metabolism. Hepatology, 66(2), 616—630. PMID 28133767 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5519435 5519435] doi:10.1002/hep.29089</ref> So, one of approaches to treating human NAFLD, obesity and metabolic syndrome via influences on host metabolism and energy is targeting in the liver the activity of the SLC13a5 gene by inhibition with '''RNAi''',<ref>Brachs, S., Winkel, A. F., Tang, H., Birkenfeld, A. L., Brunner, B., Jahn-Hofmann, K., ... & Spranger, J. (2016). Inhibition of citrate cotransporter Slc13a5/mINDY by RNAi improves hepatic insulin sensitivity and prevents diet-induced non-alcoholic fatty liver disease in mice. Molecular metabolism, 5(11), 1072-1082. PMID: 27818933 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5081411 5081411] DOI: 10.1016/j.molmet.2016.08.004</ref> '''aptamers''',<ref name="aptamers"/> '''compound 2 (PF-06649298)''', '''compound 4a''',<ref name="Potential">Willmes, D. M., Kurzbach, A., Henke, C., Schumann, T., Zahn, G., Heifetz, A., … & Birkenfeld, A. L. (2018). The longevity gene INDY (I’m Not Dead Yet) in metabolic control: Potential as pharmacological target. Pharmacology & therapeutics, 185, 1-11. PMID 28987323 Doi:[https://doi.org/10.1016/j.pharmthera.2017.10.003 10.1016/j.pharmthera.2017.10.003]</ref> '''BI01383298'''<ref name="species">Higuchi, K., Kopel, J. J., Sivaprakasam, S., Jaramillo-Martinez, V., Sutton, R. B., Urbatsch, I. L., & Ganapathy, V. (2020). Functional analysis of a species-specific inhibitor selective for human Na±coupled citrate transporter (NaCT/SLC13A5/mINDY). Biochemical Journal, 477(21), 4149-4165. PMID 33079129 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7657661 7657661] doi:10.1042/BCJ20200592</ref><ref name="interleukin"/>		Obesity and type-2 diabetes are strong [[Risk factor\|risk factors]] for metabolically associated fatty liver disease ('''MAFLD'''), also known as Non-alcoholic fatty liver disease ('''NAFLD''').<ref>Stefan, N., & Cusi, K. (2022). A global view of the interplay between non-alcoholic fatty liver disease and diabetes. The Lancet Diabetes & Endocrinology. 10(4), 284-296 DOI:[https://doi.org/10.1016/S2213-8587(22)00003-1 10.1016/S2213-8587(22)00003-1]</ref> Increased mIndy mRNA expression in the liver is strongly associated with obesity, insulin resistance, and fatty liver disease in humans.<ref name="interleukin">von Loeffelholz, C., Lieske, S., Neuschäfer‐Rube, F., Willmes, D. M., Raschzok, N., Sauer, I. M., … & Birkenfeld, A. L. (2017). The human longevity gene homolog INDY and interleukin‐6 interact in hepatic lipid metabolism. Hepatology, 66(2), 616—630. PMID 28133767 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5519435 5519435] doi:10.1002/hep.29089</ref> So, one of approaches to treating human NAFLD, obesity and metabolic syndrome via influences on host metabolism and energy is targeting in the liver the activity of the SLC13a5 gene by inhibition with '''RNAi''',<ref>Brachs, S., Winkel, A. F., Tang, H., Birkenfeld, A. L., Brunner, B., Jahn-Hofmann, K., ... & Spranger, J. (2016). Inhibition of citrate cotransporter Slc13a5/mINDY by RNAi improves hepatic insulin sensitivity and prevents diet-induced non-alcoholic fatty liver disease in mice. Molecular metabolism, 5(11), 1072-1082. PMID: 27818933 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5081411 5081411] DOI: 10.1016/j.molmet.2016.08.004</ref> '''aptamers''',<ref name="aptamers"/> '''compound 2 (PF-06649298)''', '''compound 4a''',<ref name="Potential">Willmes, D. M., Kurzbach, A., Henke, C., Schumann, T., Zahn, G., Heifetz, A., … & Birkenfeld, A. L. (2018). The longevity gene INDY (I’m Not Dead Yet) in metabolic control: Potential as pharmacological target. Pharmacology & therapeutics, 185, 1-11. PMID 28987323 Doi:[https://doi.org/10.1016/j.pharmthera.2017.10.003 10.1016/j.pharmthera.2017.10.003]</ref> '''BI01383298'''<ref name="species">Higuchi, K., Kopel, J. J., Sivaprakasam, S., Jaramillo-Martinez, V., Sutton, R. B., Urbatsch, I. L., & Ganapathy, V. (2020). Functional analysis of a species-specific inhibitor selective for human Na±coupled citrate transporter (NaCT/SLC13A5/mINDY). Biochemical Journal, 477(21), 4149-4165. PMID 33079129 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7657661 7657661] doi:10.1042/BCJ20200592</ref><ref name="interleukin"/>
	A selective, human- and multi-species-active, non-competitive, non-substrate-like inhibitor of Slc13a5/mINDY activity, called '''ETG-5773''', has also been developed.<ref name="Inhibitor">Zahn, G., Willmes, D. M., El-Agroudy, N. N., Yarnold, C., Jarjes-Pike, R., Schaertl, S., ... & Birkenfeld, A. L. (2022). A Novel and Cross-Species Active Mammalian INDY (NaCT) Inhibitor Ameliorates Hepatic Steatosis in Mice with Diet-Induced Obesity. Metabolites, 12(8), 732.PMID: 36005604 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9413491 9413491] DOI: 10.3390/metabo12080732</ref> Diet-induced obesity mouse model treated with 15 mg/kg of compound ETG-5773 twice daily within a month had reduced body weight, fasting blood glucose, and insulin, and improved glucose tolerance. Mechanistic investigation in the seven-day study showed increased plasma '''β-hydroxybutyrate''' and '''activated''' '''hepatic AMPK''' (adenosine monophosphate-activated protein kinase), reflecting findings from Indy (−/−) knockout mice.<ref name="Inhibitor"/> So, by blocking the absorption of citrate, ETG-5773 is able to combat hepatic steatosis and fatty deposits, and therefore can be used in the future for the prevention and treatment of diet-induced obesity and non-alcoholic fatty liver disease due to metabolic disorders.<ref name="Inhibitor"/>		A selective, human- and multi-species-active, non-competitive, non-substrate-like inhibitor of Slc13a5/mINDY activity, called '''ETG-5773''', has also been developed.<ref name="Inhibitor">Zahn, G., Willmes, D. M., El-Agroudy, N. N., Yarnold, C., Jarjes-Pike, R., Schaertl, S., ... & Birkenfeld, A. L. (2022). A Novel and Cross-Species Active Mammalian INDY (NaCT) Inhibitor Ameliorates Hepatic Steatosis in Mice with Diet-Induced Obesity. Metabolites, 12(8), 732.PMID: 36005604 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9413491 9413491] DOI: 10.3390/metabo12080732</ref> Diet-induced obesity mouse model treated with 15 mg/kg of compound ETG-5773 twice daily within a month had reduced body weight, fasting blood glucose, and insulin, and improved glucose tolerance. Mechanistic investigation in the seven-day study showed increased plasma '''β-hydroxybutyrate''' and '''activated''' '''hepatic AMPK''' (adenosine monophosphate-activated protein kinase), reflecting findings from Indy (−/−) knockout mice.<ref name="Inhibitor"/> So, by blocking the absorption of citrate, ETG-5773 is able to combat hepatic steatosis and fatty deposits, and therefore can be used in the future for the prevention and treatment of diet-induced obesity and non-alcoholic fatty liver disease due to metabolic disorders.<ref name="Inhibitor"/>

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	== References ==		== References ==
	<references />		<references />
	[[Category:~~Genes affecting longevity~~]]		[[Category:Main list]]
	[[Category:Longevity]]		[[Category:Longevity genes]]

Dmitry Dzhagarov: /* SLC13A5 */

2022-12-23T08:49:32Z

SLC13A5

← Older revision		Revision as of 08:49, 23 December 2022
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	==== SLC13A5 ====		==== SLC13A5 ====
	As a crucial energy sensor regulating cytosolic citrate levels, the homolog of the mammalian INDY gene ('''mINDY''') also known as '''SLC13A5 gene''' or Na<sup>+</sup>/citrate cotransporter ('''NaCT'''), plays crucial metabolic roles maintaining energy homeostasis in the liver, brain, and several other tissues.<ref name="Molecular">Mycielska, M. E., James, E. N., & Parkinson, E. K. (2022). Metabolic Alterations in Cellular Senescence: The Role of Citrate in Ageing and Age-Related Disease. International Journal of Molecular Sciences, 23(7), 3652. PMID: 35409012 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8998297 8998297] DOI:[https://doi.org/10.3390/ijms23073652 10.3390/ijms23073652]</ref><ref name="Transcription">Li, Z., & Wang, H. (2021). Molecular Mechanisms of the SLC13A5 Gene Transcription. Metabolites, 11(10), 706. PMID: 34677420 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8537064 8537064] DOI: 10.3390/metabo11100706</ref>		As a crucial energy sensor regulating cytosolic citrate levels, the homolog of the mammalian INDY gene ('''mINDY''') also known as '''SLC13A5 gene''' or Na<sup>+</sup>/citrate cotransporter ('''NaCT'''), plays crucial metabolic roles maintaining energy homeostasis in the liver, brain, and several other tissues.<ref name="Molecular">Mycielska, M. E., James, E. N., & Parkinson, E. K. (2022). Metabolic Alterations in Cellular Senescence: The Role of Citrate in Ageing and Age-Related Disease. International Journal of Molecular Sciences, 23(7), 3652. PMID: 35409012 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8998297 8998297] DOI:[https://doi.org/10.3390/ijms23073652 10.3390/ijms23073652]</ref><ref name="Transcription">Li, Z., & Wang, H. (2021). Molecular Mechanisms of the SLC13A5 Gene Transcription. Metabolites, 11(10), 706. PMID: 34677420 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8537064 8537064] DOI: 10.3390/metabo11100706</ref>
	Though both Drosophila INDY and mammalian INDY transport citrate and, to a lesser extent, succinate, malate, or fumarate, their structures differ as evident from only ~35% identity in amino acid sequence.<ref>Jaramillo-Martinez, V., Sivaprakasam, S., Ganapathy, V., & Urbatsch, I. L. (2021). Drosophila INDY and Mammalian INDY: Major Differences in Transport Mechanism and Structural Features despite Mostly Similar Biological Functions. Metabolites, 11(10), 669. PMID: 34677384 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8537002/ 8537002] DOI: 10.3390/metabo11100669</ref> The SLC13A5 gene, in addition to citrate transport, influences bile acid synthesis, nucleotide metabolism, as well as transport and synthesis of fatty acids.<ref>Milosavljevic, S., Glinton, K. E., Li, X., Medeiros, C., Gillespie, P., Seavitt, J. R., ... & Elsea, S. H. (2022). Untargeted Metabolomics of Slc13a5 Deficiency Reveal Critical Liver–Brain Axis for Lipid Homeostasis. Metabolites, 12(4), 351. PMID 35448538 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9032242 9032242] doi:10.3390/metabo12040351</ref>		Though both Drosophila INDY and mammalian INDY transport citrate and, to a lesser extent, succinate, malate, or fumarate, their structures differ as evident from only ~35% identity in amino acid sequence.<ref>Jaramillo-Martinez, V., Sivaprakasam, S., Ganapathy, V., & Urbatsch, I. L. (2021). Drosophila INDY and Mammalian INDY: Major Differences in Transport Mechanism and Structural Features despite Mostly Similar Biological Functions. Metabolites, 11(10), 669. PMID: 34677384 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8537002/ 8537002] DOI: 10.3390/metabo11100669</ref> The SLC13A5 gene, in addition to citrate transport, influences bile acid synthesis, nucleotide metabolism, as well as transport and synthesis of fatty acids. <ref name="Brain">Milosavljevic, S., Glinton, K. E., Li, X., Medeiros, C., Gillespie, P., Seavitt, J. R., ... & Elsea, S. H. (2022). Untargeted Metabolomics of Slc13a5 Deficiency Reveal Critical Liver–Brain Axis for Lipid Homeostasis. Metabolites, 12(4), 351. PMID 35448538 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9032242 9032242] doi:10.3390/metabo12040351</ref>
	In humans though beneficial effects of INDY deficiency are retained to a large extent, there is evidence for significant negative consequences, such as the devastating neurological disease known as Early Infantile Epileptic Encephalopathy-25 (EIEE-25).<ref>Kopel, J. J., Bhutia, Y. D., Sivaprakasam, S., & Ganapathy, V. (2021). Consequences of NaCT/SLC13A5/mINDY deficiency: good versus evil, separated only by the blood–brain barrier. Biochemical Journal, 478(3), 463-486. PMID: 33544126 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868109 7868109] DOI: 10.1042/BCJ20200877</ref> The effect of mINDY on health depends on age. Although SLC13A5 deficiency protects adults from obesity and diabetes, in young organisms this deficiency leads besides epileptic encephalopathy to developmental delay, thinning of tooth enamel.<ref>Klotz, J., Porter, B. E., Colas, C., Schlessinger, A., & Pajor, A. M. (2016). Mutations in the Na+/citrate cotransporter NaCT (SLC13A5) in pediatric patients with epilepsy and developmental delay. Molecular medicine, 22(1), 310-321. PMID 27261973 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5023510 5023510] doi:10.2119/molmed.2016.0007</ref><ref>Brown, T. L., Nye, K. L., & Porter, B. E. (2021). Growth and Overall Health of Patients with SLC13A5 Citrate Transporter Disorder. Metabolites, 11(11), 746. PMID 34822404 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8625967 8625967] doi:10.3390/metabo11110746</ref><ref name="Therapy">Goodspeed, K., Liu, J. S., Nye, K. L., Prasad, S., Sadhu, C., Tavakkoli, F., ... & Bailey, R. M. (2022). SLC13A5 Deficiency Disorder: From Genetics to Gene Therapy. Genes, 13(9), 1655. PMID: 36140822 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9498415 9498415] DOI: 10.3390/genes13091655</ref>		In humans though beneficial effects of INDY deficiency are retained to a large extent, there is evidence for significant negative consequences, such as the devastating neurological disease known as Early Infantile Epileptic Encephalopathy-25 (EIEE-25).<ref>Kopel, J. J., Bhutia, Y. D., Sivaprakasam, S., & Ganapathy, V. (2021). Consequences of NaCT/SLC13A5/mINDY deficiency: good versus evil, separated only by the blood–brain barrier. Biochemical Journal, 478(3), 463-486. PMID: 33544126 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868109 7868109] DOI: 10.1042/BCJ20200877</ref> The effect of mINDY on health depends on age. Although SLC13A5 deficiency protects adults from obesity and diabetes, in young organisms this deficiency leads besides epileptic encephalopathy to developmental delay, thinning of tooth enamel.<ref>Klotz, J., Porter, B. E., Colas, C., Schlessinger, A., & Pajor, A. M. (2016). Mutations in the Na+/citrate cotransporter NaCT (SLC13A5) in pediatric patients with epilepsy and developmental delay. Molecular medicine, 22(1), 310-321. PMID 27261973 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5023510 5023510] doi:10.2119/molmed.2016.0007</ref><ref>Brown, T. L., Nye, K. L., & Porter, B. E. (2021). Growth and Overall Health of Patients with SLC13A5 Citrate Transporter Disorder. Metabolites, 11(11), 746. PMID 34822404 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8625967 8625967] doi:10.3390/metabo11110746</ref><ref name="Therapy">Goodspeed, K., Liu, J. S., Nye, K. L., Prasad, S., Sadhu, C., Tavakkoli, F., ... & Bailey, R. M. (2022). SLC13A5 Deficiency Disorder: From Genetics to Gene Therapy. Genes, 13(9), 1655. PMID: 36140822 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9498415 9498415] DOI: 10.3390/genes13091655</ref>

	Loss of mINDY in MINDY<sup>-/-</sup> mice increases energy expenditure associated with increased hepatic fat oxidation and reduces hepatic lipogenesis, while surprisingly, calorie intake in MINDY-/- mice is not reduced.<ref name="adiposity">Birkenfeld, A. L., Lee, H. Y., Guebre-Egziabher, F., Alves, T. C., Jurczak, M. J., Jornayvaz, F. R., ... & Shulman, G. I. (2011). Deletion of the mammalian INDY homolog mimics aspects of dietary restriction and protects against adiposity and insulin resistance in mice. Cell metabolism, 14(2), 184-195. PMID: 21803289 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3163140 3163140] DOI: 10.1016/j.cmet.2011.06.009</ref><ref>Rogina, B. (2017). INDY—A New Link to Metabolic Regulation in Animals and Humans. Frontiers in Genetics, 8, 66. PMID: 28596784 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5442177 5442177] DOI: 10.3389/fgene.2017.00066</ref> This reduces obesity, prevents lipid accumulation in the liver and skeletal muscle, and increases insulin sensitivity under conditions of high fat diets and during aging.<ref name="adiposity"/><ref name="Transcription"/>		Loss of mINDY in MINDY<sup>-/-</sup> mice increases energy expenditure associated with increased hepatic fat oxidation and reduces hepatic lipogenesis, while surprisingly, calorie intake in MINDY-/- mice is not reduced.<ref name="adiposity">Birkenfeld, A. L., Lee, H. Y., Guebre-Egziabher, F., Alves, T. C., Jurczak, M. J., Jornayvaz, F. R., ... & Shulman, G. I. (2011). Deletion of the mammalian INDY homolog mimics aspects of dietary restriction and protects against adiposity and insulin resistance in mice. Cell metabolism, 14(2), 184-195. PMID: 21803289 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3163140 3163140] DOI: 10.1016/j.cmet.2011.06.009</ref><ref>Rogina, B. (2017). INDY—A New Link to Metabolic Regulation in Animals and Humans. Frontiers in Genetics, 8, 66. PMID: 28596784 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5442177 5442177] DOI: 10.3389/fgene.2017.00066</ref> This reduces obesity, prevents lipid accumulation in the liver and skeletal muscle, and increases insulin sensitivity under conditions of high fat diets and during aging.<ref name="adiposity"/><ref name="Transcription"/>
			Similar to what is seen in dietary restriction animals, systemic deletion of the SLC13A5 gene (mIndy knockout [KO]) significantly improves memory performance and motor coordination of mice. In addition, mice with systemic or nervous system deletion of SLC13A5 exhibit increased hippocampal neurogenesis and dendritic spine formation in dentate granule cells that also demonstrate a critical role for brain-derived mIndy in the regulation of memory function in animals.<ref>Fan, S. Z., Sung, C. W., Tsai, Y. H., Yeh, S. R., Lin, W. S., & Wang, P. Y. (2021). Nervous system deletion of mammalian INDY in mice mimics dietary restriction-induced memory enhancement. The Journals of Gerontology: Series A, 76(1), 50-56. PMID:32808644 DOI:[https://doi.org/10.1093/gerona/glaa203 10.1093/gerona/glaa203]</ref><ref name="Brain"/>

	'''Interleukin 6 (IL-6)''' can stimulate mIndy expression by binding to its cognate receptor, which induces mIndy transcription by activating the '''STAT3''' (signal transducer and activator of transcription 3) mediator protein.<ref name="interleukin">von Loeffelholz, C., Lieske, S., Neuschäfer‐Rube, F., Willmes, D. M., Raschzok, N., Sauer, I. M., … & Birkenfeld, A. L. (2017). The human longevity gene homolog INDY and interleukin‐6 interact in hepatic lipid metabolism. Hepatology, 66(2), 616—630. PMID 28133767 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5519435 5519435] doi:10.1002/hep.29089</ref> Thus, activation of the IL-6 and STAT3 signal, stimulating mIndy expression, enhances cytoplasmic citrate influx and enhances hepatic lipogenesis in vivo.<ref name="interleukin"/>		'''Interleukin 6 (IL-6)''' can stimulate mIndy expression by binding to its cognate receptor, which induces mIndy transcription by activating the '''STAT3''' (signal transducer and activator of transcription 3) mediator protein.<ref name="interleukin">von Loeffelholz, C., Lieske, S., Neuschäfer‐Rube, F., Willmes, D. M., Raschzok, N., Sauer, I. M., … & Birkenfeld, A. L. (2017). The human longevity gene homolog INDY and interleukin‐6 interact in hepatic lipid metabolism. Hepatology, 66(2), 616—630. PMID 28133767 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5519435 5519435] doi:10.1002/hep.29089</ref> Thus, activation of the IL-6 and STAT3 signal, stimulating mIndy expression, enhances cytoplasmic citrate influx and enhances hepatic lipogenesis in vivo.<ref name="interleukin"/>

Dmitry Dzhagarov at 07:58, 23 December 2022

2022-12-23T07:58:50Z

← Older revision		Revision as of 07:58, 23 December 2022
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	'''INDY''' (acronym '''I'''’m '''N'''ot '''D'''ead, '''Y'''et) is a longevity gene originally found in the fruit fly ''Drosophila melanogaster'', which encodes a plasma membrane Krebs cycle intermediate transporter.<ref>Knauf, F., Mohebbi, N., Teichert, C., Herold, D., Rogina, B., Helfand, S., ... & Aronson, P. S. (2006). The life-extending gene Indy encodes an exchanger for Krebs-cycle intermediates. Biochemical Journal, 397(1), 25-29. </ref> Defects in this gene can lead to production of a protein that renders metabolism less efficient; as a result the body functions as if the fruit fly were dieting as in [[calorie restriction]] regimen, even though its eating habits are unchanged. In natural populations of flies individuals heterozygous for the '''''Hoppel'' transposon insertion''' variant in the first intron of the Indy gene have lower Indy mRNA levels, higher fecundity and fitness advantage providing them life span extension.<ref name="transposon">Zhu, C. T., Chang, C., Reenan, R. A., & Helfand, S. L. (2014). Indy gene variation in natural populations confers fitness advantage and life span extension through transposon insertion. Aging (Albany NY), 6(1), 58. PMID: 24519859 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3927810 3927810] DOI: 10.18632/aging.100634</ref> Such '''mutations in the Indy gene in the heterozygous state result in an 80–100% increase in the average lifespan of both adult male and female fruitflies''' without sacrificing fertility or physical activity.<ref name="Rogina">Rogina, B., Reenan, R. A., Nilsen, S. P., & Helfand, S. L. (2000). Extended life-span conferred by cotransporter gene mutations in Drosophila. Science, 290(5499), 2137-2140. PMID: 11118146 DOI: 10.1126/science.290.5499.2137</ref> Heterozygous long-lived Indy females continued to produce viable adult offspring for an average of 40% longer than control flies (23.2 days versus 16.5 days).<ref name="Rogina"/> Indy long-lived flies show several phenotypes that are shared by long-lived calorie restriction flies, including '''decreased insulin-like signaling''', lipid storage, weight gain, and resistance to starvation as well as an increase in spontaneous physical activity.<ref name="calorie">Wang, P. Y., Neretti, N., Whitaker, R., Hosier, S., Chang, C., Lu, D., ... & Helfand, S. L. (2009). Long-lived Indy and calorie restriction interact to extend life span. Proceedings of the National Academy of Sciences, 106(23), 9262-9267. </ref>		'''INDY''' (acronym '''I'''’m '''N'''ot '''D'''ead, '''Y'''et) is a longevity gene originally found in the fruit fly ''Drosophila melanogaster'', which encodes a plasma membrane Krebs cycle intermediate transporter.<ref>Knauf, F., Mohebbi, N., Teichert, C., Herold, D., Rogina, B., Helfand, S., ... & Aronson, P. S. (2006). The life-extending gene Indy encodes an exchanger for Krebs-cycle intermediates. Biochemical Journal, 397(1), 25-29. </ref> Defects in this gene can lead to production of a protein that renders metabolism less efficient; as a result the body functions as if the fruit fly were dieting as in [[calorie restriction]] regimen, even though its eating habits are unchanged. In natural populations of flies individuals heterozygous for the '''''Hoppel'' [[Transposons in aging\|transposon insertion]]''' variant in the first intron of the Indy gene have lower Indy mRNA levels, higher fecundity and fitness advantage providing them life span extension.<ref name="transposon">Zhu, C. T., Chang, C., Reenan, R. A., & Helfand, S. L. (2014). Indy gene variation in natural populations confers fitness advantage and life span extension through transposon insertion. Aging (Albany NY), 6(1), 58. PMID: 24519859 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3927810 3927810] DOI: 10.18632/aging.100634</ref> Such '''mutations in the Indy gene in the heterozygous state result in an 80–100% increase in the average lifespan of both adult male and female fruitflies''' without sacrificing fertility or physical activity.<ref name="Rogina">Rogina, B., Reenan, R. A., Nilsen, S. P., & Helfand, S. L. (2000). Extended life-span conferred by cotransporter gene mutations in Drosophila. Science, 290(5499), 2137-2140. PMID: 11118146 DOI: 10.1126/science.290.5499.2137</ref> Heterozygous long-lived Indy females continued to produce viable adult offspring for an average of 40% longer than control flies (23.2 days versus 16.5 days).<ref name="Rogina"/> Indy long-lived flies show several phenotypes that are shared by long-lived calorie restriction flies, including '''decreased insulin-like signaling''', lipid storage, weight gain, and resistance to starvation as well as an increase in spontaneous physical activity.<ref name="calorie">Wang, P. Y., Neretti, N., Whitaker, R., Hosier, S., Chang, C., Lu, D., ... & Helfand, S. L. (2009). Long-lived Indy and calorie restriction interact to extend life span. Proceedings of the National Academy of Sciences, 106(23), 9262-9267. </ref>

	The molecular mechanism, by which the heterozygote advantage of Indy on longevity is mediated, involves modulation of Indy transcription<ref name="Rogina"/><ref name="calorie"/>		The molecular mechanism, by which the heterozygote advantage of Indy on longevity is mediated, involves modulation of Indy transcription<ref name="Rogina"/><ref name="calorie"/>

Dmitry Dzhagarov: /* Indy homologues */

2022-12-12T21:14:46Z

Indy homologues

← Older revision		Revision as of 21:14, 12 December 2022
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	=== Indy homologues ===		=== Indy homologues ===
	~~Indy homologues have been identified in bacteria, worms, mice, rats, dogs, rabbits, monkeys, chimpanzees, zebrafish, pigs~~ and ~~humans~~.<ref> Mishra, D., Kannan, K., Meadows, K., Macro, J., Li, M., Frankel, S., & Rogina, B. (2021). INDY—From Flies to Worms, Mice, Rats, Non-Human Primates, and Humans. Frontiers in Aging, 73. Doi:[https://doi.org/10.3389/fragi.2021.782162 10.3389/fragi.2021.782162]</ref><ref name="Kannan">Kannan, K., & Rogina, B. (2021). The Role of Citrate Transporter INDY in Metabolism and Stem Cell Homeostasis. Metabolites, 11(10), 705. Doi:[https://doi.org/10.3390/metabo11100705 10.3390/metabo11100705]</ref>		[[File:MINDY targeted interventions.jpg\|thumb\| mINDY targeted interventions to promote a healthier and longer life. According to Mishra et al. 2021<ref name="Mishra"> Mishra, D., Kannan, K., Meadows, K., Macro, J., Li, M., Frankel, S., & Rogina, B. (2021). INDY—From Flies to Worms, Mice, Rats, Non-Human Primates, and Humans. Frontiers in Aging, 73. Doi:[https://doi.org/10.3389/fragi.2021.782162 10.3389/fragi.2021.782162]</ref>]]
			Indy homologues have been identified in bacteria, worms, mice, rats, dogs, rabbits, monkeys, chimpanzees, zebrafish, pigs and humans.<ref name="Mishra"/><ref name="Kannan">Kannan, K., & Rogina, B. (2021). The Role of Citrate Transporter INDY in Metabolism and Stem Cell Homeostasis. Metabolites, 11(10), 705. Doi:[https://doi.org/10.3390/metabo11100705 10.3390/metabo11100705]</ref>

	==== SLC13A5 ====		==== SLC13A5 ====
	As a crucial energy sensor regulating cytosolic citrate levels, the homolog of the mammalian ~~Indy~~ gene ('''~~mIndy~~''') also known as '''SLC13A5 gene''' or Na<sup>+</sup>/citrate cotransporter ('''NaCT'''), plays crucial metabolic roles maintaining energy homeostasis in the liver, brain, and several other tissues.<ref name="Molecular">Mycielska, M. E., James, E. N., & Parkinson, E. K. (2022). Metabolic Alterations in Cellular Senescence: The Role of Citrate in Ageing and Age-Related Disease. International Journal of Molecular Sciences, 23(7), 3652. PMID: 35409012 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8998297 8998297] DOI:[https://doi.org/10.3390/ijms23073652 10.3390/ijms23073652]</ref><ref name="Transcription">Li, Z., & Wang, H. (2021). Molecular Mechanisms of the SLC13A5 Gene Transcription. Metabolites, 11(10), 706. PMID: 34677420 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8537064 8537064] DOI: 10.3390/metabo11100706</ref>		As a crucial energy sensor regulating cytosolic citrate levels, the homolog of the mammalian INDY gene ('''mINDY''') also known as '''SLC13A5 gene''' or Na<sup>+</sup>/citrate cotransporter ('''NaCT'''), plays crucial metabolic roles maintaining energy homeostasis in the liver, brain, and several other tissues.<ref name="Molecular">Mycielska, M. E., James, E. N., & Parkinson, E. K. (2022). Metabolic Alterations in Cellular Senescence: The Role of Citrate in Ageing and Age-Related Disease. International Journal of Molecular Sciences, 23(7), 3652. PMID: 35409012 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8998297 8998297] DOI:[https://doi.org/10.3390/ijms23073652 10.3390/ijms23073652]</ref><ref name="Transcription">Li, Z., & Wang, H. (2021). Molecular Mechanisms of the SLC13A5 Gene Transcription. Metabolites, 11(10), 706. PMID: 34677420 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8537064 8537064] DOI: 10.3390/metabo11100706</ref>
	Though both Drosophila INDY and mammalian INDY transport citrate and, to a lesser extent, succinate, malate, or fumarate, their structures differ as evident from only ~35% identity in amino acid sequence.<ref>Jaramillo-Martinez, V., Sivaprakasam, S., Ganapathy, V., & Urbatsch, I. L. (2021). Drosophila INDY and Mammalian INDY: Major Differences in Transport Mechanism and Structural Features despite Mostly Similar Biological Functions. Metabolites, 11(10), 669. PMID: 34677384 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8537002/ 8537002] DOI: 10.3390/metabo11100669</ref> The SLC13A5 gene, in addition to citrate transport, influences bile acid synthesis, nucleotide metabolism, as well as transport and synthesis of fatty acids.<ref>Milosavljevic, S., Glinton, K. E., Li, X., Medeiros, C., Gillespie, P., Seavitt, J. R., ... & Elsea, S. H. (2022). Untargeted Metabolomics of Slc13a5 Deficiency Reveal Critical Liver–Brain Axis for Lipid Homeostasis. Metabolites, 12(4), 351. PMID 35448538 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9032242 9032242] doi:10.3390/metabo12040351</ref>		Though both Drosophila INDY and mammalian INDY transport citrate and, to a lesser extent, succinate, malate, or fumarate, their structures differ as evident from only ~35% identity in amino acid sequence.<ref>Jaramillo-Martinez, V., Sivaprakasam, S., Ganapathy, V., & Urbatsch, I. L. (2021). Drosophila INDY and Mammalian INDY: Major Differences in Transport Mechanism and Structural Features despite Mostly Similar Biological Functions. Metabolites, 11(10), 669. PMID: 34677384 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8537002/ 8537002] DOI: 10.3390/metabo11100669</ref> The SLC13A5 gene, in addition to citrate transport, influences bile acid synthesis, nucleotide metabolism, as well as transport and synthesis of fatty acids.<ref>Milosavljevic, S., Glinton, K. E., Li, X., Medeiros, C., Gillespie, P., Seavitt, J. R., ... & Elsea, S. H. (2022). Untargeted Metabolomics of Slc13a5 Deficiency Reveal Critical Liver–Brain Axis for Lipid Homeostasis. Metabolites, 12(4), 351. PMID 35448538 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9032242 9032242] doi:10.3390/metabo12040351</ref>
	In humans though beneficial effects of INDY deficiency are retained to a large extent, there is evidence for significant negative consequences, such as the devastating neurological disease known as Early Infantile Epileptic Encephalopathy-25 (EIEE-25).<ref>Kopel, J. J., Bhutia, Y. D., Sivaprakasam, S., & Ganapathy, V. (2021). Consequences of NaCT/SLC13A5/mINDY deficiency: good versus evil, separated only by the blood–brain barrier. Biochemical Journal, 478(3), 463-486. PMID: 33544126 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868109 7868109] DOI: 10.1042/BCJ20200877</ref> The effect of mINDY on health depends on age. Although SLC13A5 deficiency protects adults from obesity and diabetes, in young organisms this deficiency leads besides epileptic encephalopathy to developmental delay, thinning of tooth enamel.<ref>Klotz, J., Porter, B. E., Colas, C., Schlessinger, A., & Pajor, A. M. (2016). Mutations in the Na+/citrate cotransporter NaCT (SLC13A5) in pediatric patients with epilepsy and developmental delay. Molecular medicine, 22(1), 310-321. PMID 27261973 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5023510 5023510] doi:10.2119/molmed.2016.0007</ref><ref>Brown, T. L., Nye, K. L., & Porter, B. E. (2021). Growth and Overall Health of Patients with SLC13A5 Citrate Transporter Disorder. Metabolites, 11(11), 746. PMID 34822404 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8625967 8625967] doi:10.3390/metabo11110746</ref><ref name="Therapy">Goodspeed, K., Liu, J. S., Nye, K. L., Prasad, S., Sadhu, C., Tavakkoli, F., ... & Bailey, R. M. (2022). SLC13A5 Deficiency Disorder: From Genetics to Gene Therapy. Genes, 13(9), 1655. PMID: 36140822 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9498415 9498415] DOI: 10.3390/genes13091655</ref>		In humans though beneficial effects of INDY deficiency are retained to a large extent, there is evidence for significant negative consequences, such as the devastating neurological disease known as Early Infantile Epileptic Encephalopathy-25 (EIEE-25).<ref>Kopel, J. J., Bhutia, Y. D., Sivaprakasam, S., & Ganapathy, V. (2021). Consequences of NaCT/SLC13A5/mINDY deficiency: good versus evil, separated only by the blood–brain barrier. Biochemical Journal, 478(3), 463-486. PMID: 33544126 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868109 7868109] DOI: 10.1042/BCJ20200877</ref> The effect of mINDY on health depends on age. Although SLC13A5 deficiency protects adults from obesity and diabetes, in young organisms this deficiency leads besides epileptic encephalopathy to developmental delay, thinning of tooth enamel.<ref>Klotz, J., Porter, B. E., Colas, C., Schlessinger, A., & Pajor, A. M. (2016). Mutations in the Na+/citrate cotransporter NaCT (SLC13A5) in pediatric patients with epilepsy and developmental delay. Molecular medicine, 22(1), 310-321. PMID 27261973 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5023510 5023510] doi:10.2119/molmed.2016.0007</ref><ref>Brown, T. L., Nye, K. L., & Porter, B. E. (2021). Growth and Overall Health of Patients with SLC13A5 Citrate Transporter Disorder. Metabolites, 11(11), 746. PMID 34822404 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8625967 8625967] doi:10.3390/metabo11110746</ref><ref name="Therapy">Goodspeed, K., Liu, J. S., Nye, K. L., Prasad, S., Sadhu, C., Tavakkoli, F., ... & Bailey, R. M. (2022). SLC13A5 Deficiency Disorder: From Genetics to Gene Therapy. Genes, 13(9), 1655. PMID: 36140822 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9498415 9498415] DOI: 10.3390/genes13091655</ref>

Dmitry Dzhagarov at 19:33, 12 December 2022

2022-12-12T19:33:48Z

← Older revision		Revision as of 19:33, 12 December 2022
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	'''INDY''' (acronym '''I'''’m '''N'''ot '''D'''ead, '''Y'''et) is a longevity gene originally found in the fruit fly ''Drosophila melanogaster'', which encodes a plasma membrane Krebs cycle intermediate transporter.<ref>Knauf, F., Mohebbi, N., Teichert, C., Herold, D., Rogina, B., Helfand, S., ... & Aronson, P. S. (2006). The life-extending gene Indy encodes an exchanger for Krebs-cycle intermediates. Biochemical Journal, 397(1), 25-29. </ref> Defects in this gene can lead to production of a protein that renders metabolism less efficient; as a result the body functions as if the fruit fly were dieting as in [[calorie restriction]] regimen, even though its eating habits are unchanged. ~~Several~~ '''mutations in the Indy gene in the heterozygous state result in an 80–100% increase in the average lifespan of both adult male and female fruitflies''' without sacrificing fertility or physical activity.<ref name="Rogina">Rogina, B., Reenan, R. A., Nilsen, S. P., & Helfand, S. L. (2000). Extended life-span conferred by cotransporter gene mutations in Drosophila. Science, 290(5499), 2137-2140. PMID: 11118146 DOI: 10.1126/science.290.5499.2137</ref> Heterozygous long-lived Indy females continued to produce viable adult offspring for an average of 40% longer than control flies (23.2 days versus 16.5 days).<ref name="Rogina"/> Indy long-lived flies show several phenotypes that are shared by long-lived calorie restriction flies, including '''decreased insulin-like signaling''', lipid storage, weight gain, and resistance to starvation as well as an increase in spontaneous physical activity.<ref name="calorie">Wang, P. Y., Neretti, N., Whitaker, R., Hosier, S., Chang, C., Lu, D., ... & Helfand, S. L. (2009). Long-lived Indy and calorie restriction interact to extend life span. Proceedings of the National Academy of Sciences, 106(23), 9262-9267. </ref>		'''INDY''' (acronym '''I'''’m '''N'''ot '''D'''ead, '''Y'''et) is a longevity gene originally found in the fruit fly ''Drosophila melanogaster'', which encodes a plasma membrane Krebs cycle intermediate transporter.<ref>Knauf, F., Mohebbi, N., Teichert, C., Herold, D., Rogina, B., Helfand, S., ... & Aronson, P. S. (2006). The life-extending gene Indy encodes an exchanger for Krebs-cycle intermediates. Biochemical Journal, 397(1), 25-29. </ref> Defects in this gene can lead to production of a protein that renders metabolism less efficient; as a result the body functions as if the fruit fly were dieting as in [[calorie restriction]] regimen, even though its eating habits are unchanged. In natural populations of flies individuals heterozygous for the '''''Hoppel'' transposon insertion''' variant in the first intron of the Indy gene have lower Indy mRNA levels, higher fecundity and fitness advantage providing them life span extension.<ref name="transposon">Zhu, C. T., Chang, C., Reenan, R. A., & Helfand, S. L. (2014). Indy gene variation in natural populations confers fitness advantage and life span extension through transposon insertion. Aging (Albany NY), 6(1), 58. PMID: 24519859 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3927810 3927810] DOI: 10.18632/aging.100634</ref> Such '''mutations in the Indy gene in the heterozygous state result in an 80–100% increase in the average lifespan of both adult male and female fruitflies''' without sacrificing fertility or physical activity.<ref name="Rogina">Rogina, B., Reenan, R. A., Nilsen, S. P., & Helfand, S. L. (2000). Extended life-span conferred by cotransporter gene mutations in Drosophila. Science, 290(5499), 2137-2140. PMID: 11118146 DOI: 10.1126/science.290.5499.2137</ref> Heterozygous long-lived Indy females continued to produce viable adult offspring for an average of 40% longer than control flies (23.2 days versus 16.5 days).<ref name="Rogina"/> Indy long-lived flies show several phenotypes that are shared by long-lived calorie restriction flies, including '''decreased insulin-like signaling''', lipid storage, weight gain, and resistance to starvation as well as an increase in spontaneous physical activity.<ref name="calorie">Wang, P. Y., Neretti, N., Whitaker, R., Hosier, S., Chang, C., Lu, D., ... & Helfand, S. L. (2009). Long-lived Indy and calorie restriction interact to extend life span. Proceedings of the National Academy of Sciences, 106(23), 9262-9267. </ref>

	The molecular mechanism, by which the heterozygote advantage of Indy on longevity is mediated, involves modulation of Indy transcription<ref name="Rogina"/><ref name="calorie"/>		The molecular mechanism, by which the heterozygote advantage of Indy on longevity is mediated, involves modulation of Indy transcription<ref name="Rogina"/><ref name="calorie"/>

Dmitry Dzhagarov: /* See also */

2022-12-12T19:24:03Z

Dmitry Dzhagarov: /* Inhibitor */

2022-12-12T18:23:33Z

Inhibitor

← Older revision		Revision as of 18:23, 12 December 2022
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	Although SLC13A5 deficiency protects adults from obesity and diabetes, in young organisms this deficiency leads to '''epileptic encephalopathy''' and '''developmental delay''', thinning of tooth enamel.<ref>Klotz, J., Porter, B. E., Colas, C., Schlessinger, A., & Pajor, A. M. (2016). Mutations in the Na+/citrate cotransporter NaCT (SLC13A5) in pediatric patients with epilepsy and developmental delay. Molecular medicine, 22(1), 310-321. PMID 27261973 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5023510 5023510] doi:10.2119/molmed.2016.00077</ref><ref>Brown, T. L., Nye, K. L., & Porter, B. E. (2021). Growth and Overall Health of Patients with SLC13A5 Citrate Transporter Disorder. Metabolites, 11(11), 746. PMID 34822404 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8625967 8625967] doi:10.3390/metabo11110746</ref><ref>Irizarry, A. R., Yan, G., Zeng, Q., Lucchesi, J., Hamang, M. J., Ma, Y. L., & Rong, J. X. (2017). Defective enamel and bone development in sodium-dependent citrate transporter (NaCT) Slc13a5 deficient mice. PloS one, 12(4), e0175465. PMID 28406943 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5391028 5391028] doi:10.1371/journal.pone.0175465</ref>		Although SLC13A5 deficiency protects adults from obesity and diabetes, in young organisms this deficiency leads to '''epileptic encephalopathy''' and '''developmental delay''', thinning of tooth enamel.<ref>Klotz, J., Porter, B. E., Colas, C., Schlessinger, A., & Pajor, A. M. (2016). Mutations in the Na+/citrate cotransporter NaCT (SLC13A5) in pediatric patients with epilepsy and developmental delay. Molecular medicine, 22(1), 310-321. PMID 27261973 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5023510 5023510] doi:10.2119/molmed.2016.00077</ref><ref>Brown, T. L., Nye, K. L., & Porter, B. E. (2021). Growth and Overall Health of Patients with SLC13A5 Citrate Transporter Disorder. Metabolites, 11(11), 746. PMID 34822404 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8625967 8625967] doi:10.3390/metabo11110746</ref><ref>Irizarry, A. R., Yan, G., Zeng, Q., Lucchesi, J., Hamang, M. J., Ma, Y. L., & Rong, J. X. (2017). Defective enamel and bone development in sodium-dependent citrate transporter (NaCT) Slc13a5 deficient mice. PloS one, 12(4), e0175465. PMID 28406943 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5391028 5391028] doi:10.1371/journal.pone.0175465</ref>

	=== ~~Inhibitor~~ ===		=== Inhibitors of SLC13a5 ===
	<ref>Zahn, G., Willmes, D. M., El-Agroudy, N. N., Yarnold, C., Jarjes-Pike, R., Schaertl, S., ... & Birkenfeld, A. L. (2022). A Novel and Cross-Species Active Mammalian INDY (NaCT) Inhibitor Ameliorates Hepatic Steatosis in Mice with Diet-Induced Obesity. Metabolites, 12(8), 732.PMID: 36005604 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9413491 9413491] DOI: 10.3390/metabo12080732</ref>		Studies using '''antisense oligonucleotides''' to suppress mIndy in rats have demonstrated '''an improvement in insulin sensitivity''', which has been attributed to improved hepatic glucose production and insulin sensitivity.<ref name="aptamers">Pesta, D. H., Perry, R. J., Guebre-Egziabher, F., Zhang, D., Jurczak, M., Fischer-Rosinsky, A., … & Birkenfeld, A. L. (2015). Prevention of diet-induced hepatic steatosis and hepatic insulin resistance by second generation antisense oligonucleotides targeted to the longevity gene mIndy (Slc13a5). Aging (Albany NY), 7(12), 1086. PMID 26647160 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4712334 4712334] DOI:[https://doi.org/10.18632/aging.100854 10.18632/aging.100854]</ref>

			Obesity and type 2 diabetes are strong risk factors for metabolically associated fatty liver disease ('''MAFLD'''), also known as Non-alcoholic fatty liver disease ('''NAFLD''').<ref>Stefan, N., & Cusi, K. (2022). A global view of the interplay between non-alcoholic fatty liver disease and diabetes. The Lancet Diabetes & Endocrinology. 10(4), 284-296 DOI:[https://doi.org/10.1016/S2213-8587(22)00003-1 10.1016/S2213-8587(22)00003-1]</ref> Increased mIndy mRNA expression in the liver is strongly associated with obesity, insulin resistance, and fatty liver disease in humans.<ref name="interleukin">von Loeffelholz, C., Lieske, S., Neuschäfer‐Rube, F., Willmes, D. M., Raschzok, N., Sauer, I. M., … & Birkenfeld, A. L. (2017). The human longevity gene homolog INDY and interleukin‐6 interact in hepatic lipid metabolism. Hepatology, 66(2), 616—630. PMID 28133767 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5519435 5519435] doi:10.1002/hep.29089</ref> So, one of approaches to treating human NAFLD, obesity and metabolic syndrome via influences on host metabolism and energy is targeting in the liver the activity of the SLC13a5 gene by inhibition with '''RNAi''',<ref>Brachs, S., Winkel, A. F., Tang, H., Birkenfeld, A. L., Brunner, B., Jahn-Hofmann, K., ... & Spranger, J. (2016). Inhibition of citrate cotransporter Slc13a5/mINDY by RNAi improves hepatic insulin sensitivity and prevents diet-induced non-alcoholic fatty liver disease in mice. Molecular metabolism, 5(11), 1072-1082. PMID: 27818933 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5081411 5081411] DOI: 10.1016/j.molmet.2016.08.004</ref> '''aptamers''',<ref name="aptamers"/> '''compound 2 (PF-06649298)''', '''compound 4a''',<ref name="Potential">Willmes, D. M., Kurzbach, A., Henke, C., Schumann, T., Zahn, G., Heifetz, A., … & Birkenfeld, A. L. (2018). The longevity gene INDY (I’m Not Dead Yet) in metabolic control: Potential as pharmacological target. Pharmacology & therapeutics, 185, 1-11. PMID 28987323 Doi:[https://doi.org/10.1016/j.pharmthera.2017.10.003 10.1016/j.pharmthera.2017.10.003]</ref> '''BI01383298'''<ref name="species">Higuchi, K., Kopel, J. J., Sivaprakasam, S., Jaramillo-Martinez, V., Sutton, R. B., Urbatsch, I. L., & Ganapathy, V. (2020). Functional analysis of a species-specific inhibitor selective for human Na±coupled citrate transporter (NaCT/SLC13A5/mINDY). Biochemical Journal, 477(21), 4149-4165. PMID 33079129 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7657661 7657661] doi:10.1042/BCJ20200592</ref><ref name="interleukin"/>
			A selective, human- and multi-species-active, non-competitive, non-substrate-like inhibitor of Slc13a5/mINDY activity, called '''ETG-5773''', has also been developed.<ref name="Inhibitor">Zahn, G., Willmes, D. M., El-Agroudy, N. N., Yarnold, C., Jarjes-Pike, R., Schaertl, S., ... & Birkenfeld, A. L. (2022). A Novel and Cross-Species Active Mammalian INDY (NaCT) Inhibitor Ameliorates Hepatic Steatosis in Mice with Diet-Induced Obesity. Metabolites, 12(8), 732.PMID: 36005604 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9413491 9413491] DOI: 10.3390/metabo12080732</ref> Diet-induced obesity mouse model treated with 15 mg/kg of compound ETG-5773 twice daily within a month had reduced body weight, fasting blood glucose, and insulin, and improved glucose tolerance. Mechanistic investigation in the seven-day study showed increased plasma '''β-hydroxybutyrate''' and '''activated''' '''hepatic AMPK''' (adenosine monophosphate-activated protein kinase), reflecting findings from Indy (−/−) knockout mice.<ref name="Inhibitor"/> So, by blocking the absorption of citrate, ETG-5773 is able to combat hepatic steatosis and fatty deposits, and therefore can be used in the future for the prevention and treatment of diet-induced obesity and non-alcoholic fatty liver disease due to metabolic disorders.<ref name="Inhibitor"/>

	== See also ==		== See also ==

Dmitry Dzhagarov: /* SLC13A5 */

2022-12-12T15:00:29Z

SLC13A5

← Older revision		Revision as of 15:00, 12 December 2022
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	==== SLC13A5 ====		==== SLC13A5 ====
	~~The~~ homolog of the mammalian Indy gene ('''mIndy''') also known as '''SLC13A5 gene''' or Na<sup>+</sup>/citrate cotransporter ('''NaCT'''). Though both Drosophila INDY and mammalian INDY transport citrate and, to a lesser extent, succinate, malate, or fumarate, their structures differ as evident from only ~35% identity in amino acid sequence.<ref>Jaramillo-Martinez, V., Sivaprakasam, S., Ganapathy, V., & Urbatsch, I. L. (2021). Drosophila INDY and Mammalian INDY: Major Differences in Transport Mechanism and Structural Features despite Mostly Similar Biological Functions. Metabolites, 11(10), 669. PMID: 34677384 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8537002/ 8537002] DOI: 10.3390/metabo11100669</ref> The SLC13A5 gene, in addition to citrate transport, influences bile acid synthesis, nucleotide metabolism, as well as transport and synthesis of fatty acids.<ref>Milosavljevic, S., Glinton, K. E., Li, X., Medeiros, C., Gillespie, P., Seavitt, J. R., ... & Elsea, S. H. (2022). Untargeted Metabolomics of Slc13a5 Deficiency Reveal Critical Liver–Brain Axis for Lipid Homeostasis. Metabolites, 12(4), 351. PMID 35448538 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9032242 9032242] doi:10.3390/metabo12040351</ref>		As a crucial energy sensor regulating cytosolic citrate levels, the homolog of the mammalian Indy gene ('''mIndy''') also known as '''SLC13A5 gene''' or Na<sup>+</sup>/citrate cotransporter ('''NaCT'''), plays crucial metabolic roles maintaining energy homeostasis in the liver, brain, and several other tissues.<ref name="Molecular">Mycielska, M. E., James, E. N., & Parkinson, E. K. (2022). Metabolic Alterations in Cellular Senescence: The Role of Citrate in Ageing and Age-Related Disease. International Journal of Molecular Sciences, 23(7), 3652. PMID: 35409012 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8998297 8998297] DOI:[https://doi.org/10.3390/ijms23073652 10.3390/ijms23073652]</ref><ref name="Transcription">Li, Z., & Wang, H. (2021). Molecular Mechanisms of the SLC13A5 Gene Transcription. Metabolites, 11(10), 706. PMID: 34677420 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8537064 8537064] DOI: 10.3390/metabo11100706</ref>
			Though both Drosophila INDY and mammalian INDY transport citrate and, to a lesser extent, succinate, malate, or fumarate, their structures differ as evident from only ~35% identity in amino acid sequence.<ref>Jaramillo-Martinez, V., Sivaprakasam, S., Ganapathy, V., & Urbatsch, I. L. (2021). Drosophila INDY and Mammalian INDY: Major Differences in Transport Mechanism and Structural Features despite Mostly Similar Biological Functions. Metabolites, 11(10), 669. PMID: 34677384 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8537002/ 8537002] DOI: 10.3390/metabo11100669</ref> The SLC13A5 gene, in addition to citrate transport, influences bile acid synthesis, nucleotide metabolism, as well as transport and synthesis of fatty acids.<ref>Milosavljevic, S., Glinton, K. E., Li, X., Medeiros, C., Gillespie, P., Seavitt, J. R., ... & Elsea, S. H. (2022). Untargeted Metabolomics of Slc13a5 Deficiency Reveal Critical Liver–Brain Axis for Lipid Homeostasis. Metabolites, 12(4), 351. PMID 35448538 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9032242 9032242] doi:10.3390/metabo12040351</ref>
	In humans though beneficial effects of INDY deficiency are retained to a large extent, there is evidence for significant negative consequences, such as the devastating neurological disease known as Early Infantile Epileptic Encephalopathy-25 (EIEE-25).<ref>Kopel, J. J., Bhutia, Y. D., Sivaprakasam, S., & Ganapathy, V. (2021). Consequences of NaCT/SLC13A5/mINDY deficiency: good versus evil, separated only by the blood–brain barrier. Biochemical Journal, 478(3), 463-486. PMID: 33544126 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868109 7868109] DOI: 10.1042/BCJ20200877</ref> The effect of mINDY on health depends on age. Although SLC13A5 deficiency protects adults from obesity and diabetes, in young organisms this deficiency leads besides epileptic encephalopathy to developmental delay, thinning of tooth enamel.<ref>Klotz, J., Porter, B. E., Colas, C., Schlessinger, A., & Pajor, A. M. (2016). Mutations in the Na+/citrate cotransporter NaCT (SLC13A5) in pediatric patients with epilepsy and developmental delay. Molecular medicine, 22(1), 310-321. PMID 27261973 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5023510 5023510] doi:10.2119/molmed.2016.0007</ref><ref>Brown, T. L., Nye, K. L., & Porter, B. E. (2021). Growth and Overall Health of Patients with SLC13A5 Citrate Transporter Disorder. Metabolites, 11(11), 746. PMID 34822404 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8625967 8625967] doi:10.3390/metabo11110746</ref><ref name="Therapy">Goodspeed, K., Liu, J. S., Nye, K. L., Prasad, S., Sadhu, C., Tavakkoli, F., ... & Bailey, R. M. (2022). SLC13A5 Deficiency Disorder: From Genetics to Gene Therapy. Genes, 13(9), 1655. PMID: 36140822 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9498415 9498415] DOI: 10.3390/genes13091655</ref>		In humans though beneficial effects of INDY deficiency are retained to a large extent, there is evidence for significant negative consequences, such as the devastating neurological disease known as Early Infantile Epileptic Encephalopathy-25 (EIEE-25).<ref>Kopel, J. J., Bhutia, Y. D., Sivaprakasam, S., & Ganapathy, V. (2021). Consequences of NaCT/SLC13A5/mINDY deficiency: good versus evil, separated only by the blood–brain barrier. Biochemical Journal, 478(3), 463-486. PMID: 33544126 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868109 7868109] DOI: 10.1042/BCJ20200877</ref> The effect of mINDY on health depends on age. Although SLC13A5 deficiency protects adults from obesity and diabetes, in young organisms this deficiency leads besides epileptic encephalopathy to developmental delay, thinning of tooth enamel.<ref>Klotz, J., Porter, B. E., Colas, C., Schlessinger, A., & Pajor, A. M. (2016). Mutations in the Na+/citrate cotransporter NaCT (SLC13A5) in pediatric patients with epilepsy and developmental delay. Molecular medicine, 22(1), 310-321. PMID 27261973 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5023510 5023510] doi:10.2119/molmed.2016.0007</ref><ref>Brown, T. L., Nye, K. L., & Porter, B. E. (2021). Growth and Overall Health of Patients with SLC13A5 Citrate Transporter Disorder. Metabolites, 11(11), 746. PMID 34822404 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8625967 8625967] doi:10.3390/metabo11110746</ref><ref name="Therapy">Goodspeed, K., Liu, J. S., Nye, K. L., Prasad, S., Sadhu, C., Tavakkoli, F., ... & Bailey, R. M. (2022). SLC13A5 Deficiency Disorder: From Genetics to Gene Therapy. Genes, 13(9), 1655. PMID: 36140822 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9498415 9498415] DOI: 10.3390/genes13091655</ref>

	Loss of mINDY in MINDY<sup>-/-</sup> mice increases energy expenditure associated with increased hepatic fat oxidation and reduces hepatic lipogenesis, while surprisingly, calorie intake in MINDY-/- mice is not reduced.<ref name="adiposity">Birkenfeld, A. L., Lee, H. Y., Guebre-Egziabher, F., Alves, T. C., Jurczak, M. J., Jornayvaz, F. R., ... & Shulman, G. I. (2011). Deletion of the mammalian INDY homolog mimics aspects of dietary restriction and protects against adiposity and insulin resistance in mice. Cell metabolism, 14(2), 184-195. PMID: 21803289 ~~PMCID~~: PMC3163140 DOI: 10.1016/j.cmet.2011.06.009</ref><ref>Rogina, B. (2017). INDY—A New Link to Metabolic Regulation in Animals and Humans. Frontiers in Genetics, 8, 66. PMID: 28596784 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5442177 5442177] DOI: 10.3389/fgene.2017.00066</ref> This reduces obesity, prevents lipid accumulation in the liver and skeletal muscle, and increases insulin sensitivity under conditions of high fat diets and during aging.<ref name="adiposity"/>		Loss of mINDY in MINDY<sup>-/-</sup> mice increases energy expenditure associated with increased hepatic fat oxidation and reduces hepatic lipogenesis, while surprisingly, calorie intake in MINDY-/- mice is not reduced.<ref name="adiposity">Birkenfeld, A. L., Lee, H. Y., Guebre-Egziabher, F., Alves, T. C., Jurczak, M. J., Jornayvaz, F. R., ... & Shulman, G. I. (2011). Deletion of the mammalian INDY homolog mimics aspects of dietary restriction and protects against adiposity and insulin resistance in mice. Cell metabolism, 14(2), 184-195. PMID: 21803289 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3163140 3163140] DOI: 10.1016/j.cmet.2011.06.009</ref><ref>Rogina, B. (2017). INDY—A New Link to Metabolic Regulation in Animals and Humans. Frontiers in Genetics, 8, 66. PMID: 28596784 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5442177 5442177] DOI: 10.3389/fgene.2017.00066</ref> This reduces obesity, prevents lipid accumulation in the liver and skeletal muscle, and increases insulin sensitivity under conditions of high fat diets and during aging.<ref name="adiposity"/><ref name="Transcription"/>

	'''Interleukin 6 (IL-6)''' can stimulate mIndy expression by binding to its cognate receptor, which induces mIndy transcription by activating the '''STAT3''' (signal transducer and activator of transcription 3) mediator protein.<ref name="interleukin">von Loeffelholz, C., Lieske, S., Neuschäfer‐Rube, F., Willmes, D. M., Raschzok, N., Sauer, I. M., … & Birkenfeld, A. L. (2017). The human longevity gene homolog INDY and interleukin‐6 interact in hepatic lipid metabolism. Hepatology, 66(2), 616—630. PMID 28133767 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5519435 5519435] doi:10.1002/hep.29089</ref> Thus, activation of the IL-6 and STAT3 signal, stimulating mIndy expression, enhances cytoplasmic citrate influx and enhances hepatic lipogenesis in vivo.<ref name="interleukin"/>		'''Interleukin 6 (IL-6)''' can stimulate mIndy expression by binding to its cognate receptor, which induces mIndy transcription by activating the '''STAT3''' (signal transducer and activator of transcription 3) mediator protein.<ref name="interleukin">von Loeffelholz, C., Lieske, S., Neuschäfer‐Rube, F., Willmes, D. M., Raschzok, N., Sauer, I. M., … & Birkenfeld, A. L. (2017). The human longevity gene homolog INDY and interleukin‐6 interact in hepatic lipid metabolism. Hepatology, 66(2), 616—630. PMID 28133767 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5519435 5519435] doi:10.1002/hep.29089</ref> Thus, activation of the IL-6 and STAT3 signal, stimulating mIndy expression, enhances cytoplasmic citrate influx and enhances hepatic lipogenesis in vivo.<ref name="interleukin"/>

← Older revision		Revision as of 19:24, 12 December 2022
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	== See also ==		== See also ==
	* <ref name="transposon">Zhu, C. T., Chang, C., Reenan, R. A., & Helfand, S. L. (2014). Indy gene variation in natural populations confers fitness advantage and life span extension through transposon insertion. Aging (Albany NY), 6(1), 58. PMID: 24519859 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3927810 3927810] DOI: 10.18632/aging.100634</ref>
	* <ref name="Cardio">Pesta, D., & Jordan, J. (2022). INDY as a Therapeutic Target for Cardio-Metabolic Disease. Metabolites, 12(3), 244. PMID: 35323687 PMCID: PMC8949283 DOI: 10.3390/metabo12030244</ref>		* <ref name="Cardio">Pesta, D., & Jordan, J. (2022). INDY as a Therapeutic Target for Cardio-Metabolic Disease. Metabolites, 12(3), 244. PMID: 35323687 PMCID: PMC8949283 DOI: 10.3390/metabo12030244</ref>
	* Mycielska, M. E., James, E. N., & Parkinson, E. K. (2022). Metabolic Alterations in Cellular Senescence: The Role of Citrate in Ageing and Age-Related Disease. International Journal of Molecular Sciences, 23(7), 3652. PMID: 35409012 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8998297 8998297] DOI: 10.3390/ijms23073652
	* Brachs, S., Winkel, A. F., Tang, H., Birkenfeld, A. L., Brunner, B., Jahn-Hofmann, K., ... & Spranger, J. (2016). Inhibition of citrate cotransporter Slc13a5/mINDY by RNAi improves hepatic insulin sensitivity and prevents diet-induced non-alcoholic fatty liver disease in mice. Molecular metabolism, 5(11), 1072-1082. PMID: 27818933 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5081411 5081411] DOI: 10.1016/j.molmet.2016.08.004
	* Zahn, G., Willmes, D. M., El-Agroudy, N. N., Yarnold, C., Jarjes-Pike, R., Schaertl, S., ... & Birkenfeld, A. L. (2022). A Novel and Cross-Species Active Mammalian INDY (NaCT) Inhibitor Ameliorates Hepatic Steatosis in Mice with Diet-Induced Obesity. Metabolites, 12(8), 732. PMID: 36005604 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9413491 9413491] DOI: 10.3390/metabo12080732

	== References ==		== References ==