RNA-binding protein hnRNPR reduces cholesterol levels by binding to and suppressing HMGCR

Heterogeneous nuclear ribonucleoproteins (hnRNPs) represent a large family of RNA-binding proteins (RBPs) that are actively involved in RNA metabolism, including alternative splicing, mRNA stability, and gene expression control at transcriptional and post-transcriptional levels. Recent studies have identified multiple RBPs that are tightly associated with lipid and cholesterol metabolism and cardiovascular disorders. However, the role of heterogeneous nuclear ribonucleoprotein R (hnRNPR) in cholesterol metabolism and homeostasis, whether it has a role in the regulation of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) is largely unknown. This study identifies hnRNPR as a repressor of HMGCR. Knockdown and overexpression of hnRNPR in cultured neuroblastoma cell (N2A) and MN1 cell lines enhances and inhibits HMGCR in vitro, respectively. hnRNPR may exert its repressive activity on HMGCR mRNA and protein levels by using its RNA recognition motif (RRM) in recognizing and modulating the stability of HMGCR transcript. Our RNA immunoprecipitation and luciferase reporter assays demonstrate a direct interaction between hnRNPR and HMGCR mRNA. We also demonstrated that hnRNR binds to the 3′untranslated region (3’UTR) of HMGCR and reduces its translation, while hnRNPR silencing increases HMGCR expression and cholesterol level in MN1 and N2a cells. Overexpression of HMGCR significantly restores the decreased cholesterol levels in hnRNPR administered cells. Taken together, we identify hnRNPR as a novel post-transcriptional regulator of HMGCR expression in neuronal cholesterol homeostasis. These data suggest that modulation of cholesterol by hnRNPR could open new vistas in understanding the physiology, pathogenesis, and pharmacotherapy of cholesterol-related disorders caused by dysfunction of cholesterol homeostasis.