LY6D drives hepatic steatosis by activating the `GRB2-AMPK-SREBP1c` axis, suggesting a novel target for **MASLD**.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disease globally, often progressing to more severe forms like metabolic dysfunction-associated steatohepatitis (MASH). While recent FDA approvals for Resmetirom and Semaglutide offer therapeutic options, their efficacy is limited to a subset of patients, highlighting an urgent need for novel molecular targets. Understanding new pathways that drive hepatic lipid accumulation is crucial for developing broader and more effective treatments for MASLD pathogenesis. This study investigates lymphocyte antigen 6 complex locus D (LY6D) as a potential contributor to liver fat accumulation.

Researchers assessed LY6D expression in liver tissue from MASLD patients and validated findings in ob/ob and db/db leptin-deficient mice, alongside high-fat diet-fed mouse models. Transcriptomic profiling via RNA sequencing identified LY6D-associated metabolic pathways. Functional analyses in LY6D-overexpressing mice evaluated hepatic lipid content, gene expression, and protein signaling. Protein-protein interactions were determined using co-immunoprecipitation, while AMPK phosphorylation at Thr172 and SREBP1 activation were measured by Western blotting.

LY6D expression was significantly elevated in liver samples from MASLD patients and in all tested mouse models of hepatic steatosis. Transcriptomic analysis via RNA sequencing revealed a strong enrichment of fatty acid synthesis pathways in livers with high LY6D expression. In LY6D-overexpressing mice, de novo lipogenesis was increased, accompanied by the upregulation of key lipogenic genes, including Srebf1, Fasn, Acaca, and Scd1. > Mechanistically, LY6D was found to associate with growth factor receptor-bound protein 2 (GRB2), which led to reduced AMPK phosphorylation at Thr172. Further, modulating AMPK activity directly altered LY6D-dependent SREBP1c abundance and its nuclear accumulation, confirming an LY6D-associated GRB2-AMPK-SREBP1c regulatory node that actively promotes hepatic steatosis.