Genetic inactivation of zinc transporter SLC39A5 improves liver function and hyperglycemia in obesogenic settings
Recent studies have revealed a role for zinc in insulin secretion and glucose homeostasis. Randomized placebo-controlled zinc supplementation trials have demonstrated improved glycemic traits in patients with type II diabetes (T2D). Moreover, rare loss-of-function variants in the zinc efflux transpo...
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eLife Sciences Publications Ltd
2024-12-01
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| Online Access: | https://elifesciences.org/articles/90419 |
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| author | Shek Man Chim Kristen Howell John Dronzek Weizhen Wu Cristopher Van Hout Manuel AR Ferreira Bin Ye Alexander Li Susannah Brydges Vinayagam Arunachalam Anthony Marcketta Adam E Locke Jonas Bovijn Niek Verweij Tanima De Luca Lotta Lyndon Mitnaul Michelle LeBlanc Regeneron Genetics Center David J Carey Olle Melander Alan Shuldiner Katia Karalis Aris N Economides Harikiran Nistala DiscovEHR collaboration Regeneron Genetics Center |
| author_facet | Shek Man Chim Kristen Howell John Dronzek Weizhen Wu Cristopher Van Hout Manuel AR Ferreira Bin Ye Alexander Li Susannah Brydges Vinayagam Arunachalam Anthony Marcketta Adam E Locke Jonas Bovijn Niek Verweij Tanima De Luca Lotta Lyndon Mitnaul Michelle LeBlanc Regeneron Genetics Center David J Carey Olle Melander Alan Shuldiner Katia Karalis Aris N Economides Harikiran Nistala DiscovEHR collaboration Regeneron Genetics Center |
| author_sort | Shek Man Chim |
| collection | DOAJ |
| description | Recent studies have revealed a role for zinc in insulin secretion and glucose homeostasis. Randomized placebo-controlled zinc supplementation trials have demonstrated improved glycemic traits in patients with type II diabetes (T2D). Moreover, rare loss-of-function variants in the zinc efflux transporter SLC30A8 reduce T2D risk. Despite this accumulated evidence, a mechanistic understanding of how zinc influences systemic glucose homeostasis and consequently T2D risk remains unclear. To further explore the relationship between zinc and metabolic traits, we searched the exome database of the Regeneron Genetics Center-Geisinger Health System DiscovEHR cohort for genes that regulate zinc levels and associate with changes in metabolic traits. We then explored our main finding using in vitro and in vivo models. We identified rare loss-of-function (LOF) variants (MAF <1%) in Solute Carrier Family 39, Member 5 (SLC39A5) associated with increased circulating zinc (p=4.9 × 10-4). Trans-ancestry meta-analysis across four studies exhibited a nominal association of SLC39A5 LOF variants with decreased T2D risk. To explore the mechanisms underlying these associations, we generated mice lacking Slc39a5. Slc39a5-/- mice display improved liver function and reduced hyperglycemia when challenged with congenital or diet-induced obesity. These improvements result from elevated hepatic zinc levels and concomitant activation of hepatic AMPK and AKT signaling, in part due to zinc-mediated inhibition of hepatic protein phosphatase activity. Furthermore, under conditions of diet-induced non-alcoholic steatohepatitis (NASH), Slc39a5-/- mice display significantly attenuated fibrosis and inflammation. Taken together, these results suggest SLC39A5 as a potential therapeutic target for non-alcoholic fatty liver disease (NAFLD) due to metabolic derangements including T2D. |
| format | Article |
| id | doaj-art-4cfb8adbbf2e476a8a97ea22b5553ed1 |
| institution | OA Journals |
| issn | 2050-084X |
| language | English |
| publishDate | 2024-12-01 |
| publisher | eLife Sciences Publications Ltd |
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| series | eLife |
| spelling | doaj-art-4cfb8adbbf2e476a8a97ea22b5553ed12025-08-20T01:55:37ZengeLife Sciences Publications LtdeLife2050-084X2024-12-011210.7554/eLife.90419Genetic inactivation of zinc transporter SLC39A5 improves liver function and hyperglycemia in obesogenic settingsShek Man Chim0https://orcid.org/0000-0002-5116-8394Kristen Howell1John Dronzek2Weizhen Wu3Cristopher Van Hout4Manuel AR Ferreira5Bin Ye6Alexander Li7Susannah Brydges8Vinayagam Arunachalam9Anthony Marcketta10Adam E Locke11https://orcid.org/0000-0001-6227-198XJonas Bovijn12Niek Verweij13Tanima De14Luca Lotta15Lyndon Mitnaul16Michelle LeBlanc17Regeneron Genetics Center18David J Carey19Olle Melander20Alan Shuldiner21Katia Karalis22Aris N Economides23https://orcid.org/0000-0002-6508-8942Harikiran Nistala24https://orcid.org/0000-0003-4928-7527DiscovEHR collaborationRegeneron Genetics CenterRegeneron Genetics Center, New York, United StatesRegeneron Genetics Center, New York, United StatesRegeneron Genetics Center, New York, United StatesRegeneron Genetics Center, New York, United StatesRegeneron Genetics Center, New York, United StatesRegeneron Genetics Center, New York, United StatesRegeneron Genetics Center, New York, United StatesRegeneron Genetics Center, New York, United StatesRegeneron Pharmaceuticals, New York, United StatesRegeneron Genetics Center, New York, United StatesRegeneron Genetics Center, New York, United StatesRegeneron Genetics Center, New York, United StatesRegeneron Genetics Center, New York, United StatesRegeneron Genetics Center, New York, United StatesRegeneron Genetics Center, New York, United StatesRegeneron Genetics Center, New York, United StatesRegeneron Genetics Center, New York, United StatesRegeneron Genetics Center, New York, United StatesRegeneron Genetics Center, New York, United StatesGeisinger Health System, Danville, United StatesDepartment of Clinical Sciences, Malmö, SwedenRegeneron Genetics Center, New York, United StatesRegeneron Genetics Center, New York, United StatesRegeneron Genetics Center, New York, United States; Regeneron Pharmaceuticals, New York, United StatesRegeneron Genetics Center, New York, United StatesRecent studies have revealed a role for zinc in insulin secretion and glucose homeostasis. Randomized placebo-controlled zinc supplementation trials have demonstrated improved glycemic traits in patients with type II diabetes (T2D). Moreover, rare loss-of-function variants in the zinc efflux transporter SLC30A8 reduce T2D risk. Despite this accumulated evidence, a mechanistic understanding of how zinc influences systemic glucose homeostasis and consequently T2D risk remains unclear. To further explore the relationship between zinc and metabolic traits, we searched the exome database of the Regeneron Genetics Center-Geisinger Health System DiscovEHR cohort for genes that regulate zinc levels and associate with changes in metabolic traits. We then explored our main finding using in vitro and in vivo models. We identified rare loss-of-function (LOF) variants (MAF <1%) in Solute Carrier Family 39, Member 5 (SLC39A5) associated with increased circulating zinc (p=4.9 × 10-4). Trans-ancestry meta-analysis across four studies exhibited a nominal association of SLC39A5 LOF variants with decreased T2D risk. To explore the mechanisms underlying these associations, we generated mice lacking Slc39a5. Slc39a5-/- mice display improved liver function and reduced hyperglycemia when challenged with congenital or diet-induced obesity. These improvements result from elevated hepatic zinc levels and concomitant activation of hepatic AMPK and AKT signaling, in part due to zinc-mediated inhibition of hepatic protein phosphatase activity. Furthermore, under conditions of diet-induced non-alcoholic steatohepatitis (NASH), Slc39a5-/- mice display significantly attenuated fibrosis and inflammation. Taken together, these results suggest SLC39A5 as a potential therapeutic target for non-alcoholic fatty liver disease (NAFLD) due to metabolic derangements including T2D.https://elifesciences.org/articles/90419Type II diabetesNAFLDzinc transporter |
| spellingShingle | Shek Man Chim Kristen Howell John Dronzek Weizhen Wu Cristopher Van Hout Manuel AR Ferreira Bin Ye Alexander Li Susannah Brydges Vinayagam Arunachalam Anthony Marcketta Adam E Locke Jonas Bovijn Niek Verweij Tanima De Luca Lotta Lyndon Mitnaul Michelle LeBlanc Regeneron Genetics Center David J Carey Olle Melander Alan Shuldiner Katia Karalis Aris N Economides Harikiran Nistala DiscovEHR collaboration Regeneron Genetics Center Genetic inactivation of zinc transporter SLC39A5 improves liver function and hyperglycemia in obesogenic settings eLife Type II diabetes NAFLD zinc transporter |
| title | Genetic inactivation of zinc transporter SLC39A5 improves liver function and hyperglycemia in obesogenic settings |
| title_full | Genetic inactivation of zinc transporter SLC39A5 improves liver function and hyperglycemia in obesogenic settings |
| title_fullStr | Genetic inactivation of zinc transporter SLC39A5 improves liver function and hyperglycemia in obesogenic settings |
| title_full_unstemmed | Genetic inactivation of zinc transporter SLC39A5 improves liver function and hyperglycemia in obesogenic settings |
| title_short | Genetic inactivation of zinc transporter SLC39A5 improves liver function and hyperglycemia in obesogenic settings |
| title_sort | genetic inactivation of zinc transporter slc39a5 improves liver function and hyperglycemia in obesogenic settings |
| topic | Type II diabetes NAFLD zinc transporter |
| url | https://elifesciences.org/articles/90419 |
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