YAP/TAZ knockdown reduces lipid droplet accumulation in hepatic cells through a putative SBDSP1/miR-29a-5p/LDLR...

Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) are central downstream effectors of the Hippo pathway and play key roles in hepatic metabolic regulation. However, the molecular mechanisms by which YAP/TAZ modulate lipid processing in hepatocytes remain incompletely understood. In this study, we investigated a YAP/TAZ-dependent non-coding RNA regulatory network controlling low-density lipoprotein receptor (LDLR) expression and lipid droplet accumulation in human hepatic cells. Using transcriptomic profiling combined with functional validation in human hepatocellular carcinoma cells, we identified the long non-coding RNA Shwachman-Bodian-Diamond Syndrome Pseudogene 1 (SBDSP1) as a YAP/TAZ-downstream transcript that positively regulates LDLR expression. Silencing of YAP/TAZ significantly reduced SBDSP1 levels, accompanied by downregulation of LDLR mRNA and protein, impaired LDL uptake, and reduced intracellular lipid droplet accumulation. Mechanistically, SBDSP1 was predicted to interact with miR-29a-5p, a microRNA putatively targeting the 3' untranslated region of LDLR. Knockdown of SBDSP1 or mimicking of miR-29a-5p decreased LDLR expression and reduced lipid accumulation, while luciferase reporter assays confirmed direct interactions between miR-29a-5p and both SBDSP1 and LDLR. Collectively, these findings describe a potential YAP/TAZ-SBDSP1-miR-29a-5p-LDLR regulatory axis that controls hepatic lipid uptake and accumulation. This study provides molecular insights into the interplay between Hippo pathway signaling and non-coding RNA networks to regulate lipid metabolism, highlighting a potential regulatory mechanism that may be relevant to hepatic lipid accumulation in metabolic dysfunction-associated steatotic liver disease.