ZIP8, an essential nutrient membrane transporter, is also a clinically important target associated with metabolic traits, such as HDL-cholesterol levels and body-mass index (BMI). However, the connection between ZIP8 and specific metabolic pathways has not been elucidated. The overall goal of this proposal is to identify a unique function of ZIP8 in the regulation of methionine metabolism, which deficiency was reported to elevate lipid levels and induce multiple liver diseases. ZIP8 is a multi-functional electroneutral membrane transporter, which transports beneficial (Zn, Mn and Fe) and toxic metals (Cd). We previously reported that ZIP8 is a major transporter for anionic selenite (HSeO3?) with zinc and bicarbonate serving as co-substrates (McDermott, 2016). We recently discovered that chronic ZIP8 deficiency-induced hepatic pathology including fatty liver disease (Liu, 2018). To identify ZIP8-regulated pathways that underlie the observed liver pathologies, we performed RNA-seq analysis in ZIP8 hypomorphic mouse liver. Our transcriptome profiling analysis identified the methionine metabolism pathway a major target that is downregulated by ZIP8 deficiency with BHMT1, MAT1A, and MAT2A being significantly altered in ZIP8 hypomorphic mice. Furthermore, we also discovered that ZIP8 regulates hepatic selenium homeostasis, which might serve as a key mediator of ZIP8-associated changes in the methionine pathway and liver pathologies. Based on these observations, we hypothesize that ZIP8 controls liver selenium homeostasis and regulates the methionine pathway, leading to metabolic disorders when ZIP8 is deficient. We will test our hypothesis through three specific aims, using in vitro and in vivo models with altered ZIP8 expression. Specifically, we will: 1) determine the role of ZIP8 in controlling methionine pathway intermediates and enzymes including BHMT1, MAT1A/2A, MS and CBS in ZIP8-altered hepatocytes, 2) determine ZIP8 physiological and pathological function in ZIP8- liver-specific knockout mice under methionine-choline deficiency stress, and 3) determine the role of ZIP8 in regulating liver selenium homeostasis with Se-supplementing and deficient diet in cells and in ZIP8-liver-specific knockout mice. The successful completion of this project will identify ZIP8 regulated targets: the methionine pathway and selenium transport; and help elucidate the roles of ZIP8 in normal liver function.
The role of ZIP8 in regulating liver methionine metabolism and selenium homeostasis in ZIP8- gain and loss hepatocytes and ZIP8- liver-specific knockout mice will be elucidated. Our results will furnish mechanistic insights into how ZIP8 deficiency leads to metabolic disorders.
