The LEPIS-HuR-TMOD4 axis regulates hepatic cholesterol homeostasis and accelerates atherosclerosis

Long noncoding RNAs (lncRNAs) play an important role in the entire progression of atherosclerosis. In this study, we identified an uncharacterized lncRNA, Liver Expressions by PSRC1 Induce Specifically (LEPIS). The expression of LEPIS and its potential target tropomodulin 4 (TMOD4) in the liver of ApoE-/- mice fed a high-fat diet was increased. An ApoE-/- mouse model with the overexpression of LEPIS or TMOD4 in liver was established, and we found that both LEPIS and TMOD4 increased the burden of atherosclerosis and reduced hepatic cholesterol levels. Further study revealed that LEPIS and TMOD4 affect the expression of genes related to hepatic cholesterol homeostasis, including proprotein convertase subtilisin/kexin type9 (PCSK9) and low-density lipoprotein receptor (LDLR), which are closely related to hypercholesterolemia. Mechanistically, human antigen R (HuR), an RNA-binding protein, was shown to be critical for the regulation of TMOD4 by LEPIS. Further, we found that overexpression of LEPIS promoted the shuttling of HuR from the nucleus to the cytoplasm, enhanced the stability of TMOD4 mRNA, and in turn promoted the expression of TMOD4. In addition, TMOD4 was found to affect intracellular cholesterol levels through PCSK9. These results suggest that the LEPIS-HuR-TMOD4 axis is a potential intervention target for hepatic cholesterol homeostasis and atherosclerosis. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=183 SRC="FIGDIR/small/490400v1_ufig1.gif" ALT="Figure 1"> View larger version (59K): org.highwire.dtl.DTLVardef@c4af60org.highwire.dtl.DTLVardef@d5e7d1org.highwire.dtl.DTLVardef@1667d08org.highwire.dtl.DTLVardef@19abddd_HPS_FORMAT_FIGEXP M_FIG C_FIG