| Summary: | Recent studies have identified
multiple RNA-binding proteins tightly associated with lipid and neuronal 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 regulating 3-hydroxy-3-methyl-glutaryl-coenzyme A
reductase (HMGCR), is largely unknown. This research 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 levels 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.
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