Genetic inactivation of zinc transporter SLC39A5 improves liver function and hyperglycemia in obesogenic settings

AbstractBackground &amp; AimsRecent studies have revealed a role for zinc in insulin secretion and systemic glucose homeostasis. Randomized placebo-controlled zinc supplementation trials have demonstrated improved glycemic traits in patients with type II diabetes (T2D). Moreover, carriers of rare loss-of-function variants in the zinc efflux transporter SLC30A8 have been reported to reduce T2D risk. Despite this accumulated evidence, mechanistic understanding of how zinc influences systemic glucose homeostasis and consequently T2D risk remains unclear.MethodsTo 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.ResultsWe identified rare loss-of-function (LOF) variants (MAF&lt;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 nominal association of SLC39A5 LOF variants with decreased T2D risk (OR 0.82, 95%CI 0.68-0.99, p=3.7×10-2). To explore the mechanistic aspects of 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.ConclusionsTaken together, these results suggest SLC39A5 as a potential therapeutic target for non-alcoholic fatty liver disease (NAFLD) and consequent metabolic derangements including T2D.Lay summaryZinc is an essential trace element in human health. We identified mutations in a zinc transporter gene, SLC39A5 that are associated with increased circulating zinc and nominal reduction in type II diabetes risk in humans. To understand this connection we generated mice lacking this gene and showed that they have improved liver function and reduced hyperglycemia under obesogenic conditions and also when given a diet that causes fatty liver disease. Our observations suggest that pharmacological inhibition of SLC39A5 may be a potential therapeutic avenue for type II diabetes and non-alcoholic fatty liver disease.Graphical abstractManuscript HighlightsHeterozygous loss-of-function mutations in SLC39A5 associated with elevated circulating zinc levels and nominal reduction in type II diabetes risk in humans.Loss of Slc39a5 results in elevated circulating and hepatic zinc levels in mice.Mice lacking Slc39a5 function are protected against hepatic steatosis and hyperglycemia resulting from diet-induced obesity or leptin-receptor deficiency and display reduced hepatic inflammation and fibrosis resulting from diet-induced NASH.Loss of Slc39a5 function results in hepatic AMPK and AKT activation.SLC39A5 is a potential therapeutic target for fatty liver disease and type II diabetes.</jats:sec

Whole genome sequencing reveals hidden transmission of carbapenemase-producing Enterobacterales

AbstractCarbapenemase-producing Enterobacterales (CPE) infection control practices are based on the paradigm that detected carriers in the hospital transmit to other patients who stay in the same ward. The role of plasmid-mediated transmission at population level remains largely unknown. In this retrospective cohort study over 4.7 years involving all multi-disciplinary public hospitals in Singapore, we analysed 779 patients who acquired CPE (1215 CPE isolates) detected by clinical or surveillance cultures. 42.0% met putative clonal transmission criteria, 44.8% met putative plasmid-mediated transmission criteria and 13.2% were unlinked. Only putative clonal transmissions associated with direct ward contact decreased in the second half of the study. Both putative clonal and plasmid-mediated transmission associated with indirect (no temporal overlap in patients’ admission period) ward and hospital contact did not decrease during the study period. Indirect ward and hospital contact were identified as independent risk factors associated with clonal transmission. In conclusion, undetected CPE reservoirs continue to evade hospital infection prevention measures. New measures are needed to address plasmid-mediated transmission, which accounted for 50% of CPE dissemination.</jats:p