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.