Metabolic dysfunction-associated steatotic liver disease (MASLD), previously termed nonalcoholic fatty liver disease (NAFLD), is the most common chronic liver disease in the United States and a rapidly growing cause of morbidity, mortality, and need for liver transplantation. Therefore, there is a critical need for effective therapies for this increasingly common yet heterogeneous disease. An under-explored area in the field is the role of the nuclear envelope and lamina, which together form a structural and functional link between the cytoskeleton and genome in all nucleated cells, regulating chromatin accessibility, gene transcription, and transport of RNA and proteins across the nuclear membrane to maintain cellular and organismal homeostasis. As part of our NIDDK K08-funded work, we have identified a common coding variant in SUN1, encoding a ubiquitously expressed inner nuclear membrane protein, that positively associates with hepatic steatosis, histologic MASLD, and MASLD-related metabolic traits in multiple large cohorts. This variant, altering a charged residue in the nucleoplasmic portion of the protein, increased SUN1 proteasomal degradation and led to insulin resistance and increased lipid accumulation in transfected cells. Collectively, these findings suggest that SUN1 plays a role in protecting against MASLD and metabolic disease and that SUN1 variants may contribute to MASLD at a population level. In this proposal, we hypothesize that SUN1 protects against MASLD and metabolic disease via effects in multiple cell and tissue types in vivo, with protective effects in both hepatocytes and adipocytes, and that SUN1 H118Y – and other SUN1 variants – likely have deleterious impacts in multiple cell and tissue types. Using stable SUN1-expressing cell lines that we are generating, and biochemical techniques that we already have established, we aim to determine the cell types in which, and mechanisms by which, SUN1 H118Y exerts MASLD-promoting metabolic effects (Aim 1). In parallel, we will utilize newly available whole exome sequence data from UK Biobank to identify additional variants in SUN1 that associate with MASLD (Aim 2). Collectively, these studies will advance our understanding of nuclear envelope-related metabolic disease and MASLD and the mechanisms by which SUN1, which is a potential new therapeutic target in MASLD, protects against liver disease. Additionally, the studies proposed will build toward an R01 application focused on the role of SUN1, and the effects of SUN1 H118Y, in MASLD-relevant metabolic pathways in multiple tissue types in vivo.