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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., Competing Interests: SC, KH, JD, WW, MF, BY, AL, SB, VA, AM, AL, JB, NV, TD, LM, ML, RC, AS, AE, HN full-time employee of the Regeneron Genetics Center or Regeneron Pharmaceuticals Inc and hold stock options/restricted stock as part of compensation, CV, DC, OM, KK No competing interests declared, LL full-time employee of the Regeneron Genetics Center or Regeneron Pharmaceuticals Inc and hold stock options/restricted stock as part of compensation.full-time employee of the Regeneron Genetics Center or Regeneron Pharmaceuticals Inc and hold stock options/restricted stock as part of compensation, (© 2023, Chim et al.)