Abstract 440: Role Of Retinoid X Receptor In Regulating Pcsk9 Transcription In The Liver And Atherosclerosis

Abstract

Nonalcoholic fatty liver diseases ( NALFD) are associated with high cardiovascular disease ( CVD ) risk. The demand for novel CVD treatments leads to the recent discovery of the Proprotein Convertase Subtilisin Kexin 9 ( PCSK9 ), which promotes the degradation of low-density lipoprotein receptor ( LDLR ) to increase atherogenic lipoprotein LDL cholesterol ( LDL-C ) levels. Targeting PCSK9 shows promising benefits in mitigating CVD and NAFLD. However, the underlying mechanism causing the NAFLD-associated PCSK9 induction is still unclear. Our findings fill the critical knowledge gap by elucidating that Retinoid X Receptor alpha ( RXRα ) is essential to regulate the transcription of PCSK9 in the liver. Our preliminary data showed that hepatic depletion of RXRα leads to hepatic steatosis. To reveal the underlying mechanism by which hepatic RXRα deficiency promotes NAFLD development, we carried out the RNA-seq analysis. The Gene Set Enrichment Analysis ( GSEA ) of RNA-seq data showed the expected downregulation of PPARα signaling genes and the unexpected upregulation of cholesterol pathway genes in the liver of RXRα hepatocyte-specific knockout ( hepKO ) mice. One of the significantly upregulated genes in the cholesterol pathway is PCSK9, which induction in the liver of RXRα hepKO mice can be abolished by AAV8-mediated overexpression of RXRα. Consistently, we observed the increased cholesterol and LDL-C in the plasma of RXRα hepKO mice, and hepatic overexpression of RXRα can significantly reduce the plasma cholesterol and LDL-C levels. Recently, we identified a previously unrecognized acetylation residue of RXRα, which controls the heterodimerization between RXRα and PPARα. The inhibitory effects of constitutively acetylated RXRα mutant further indicate that acetylation of RXRα is essential for preventing the induction of PCSK9 in the liver of RXRα hepKO mice. Interestingly, we also observed the decreased acetylation of RXRα in the liver of high-fat diet ( HFD )-fed mice and human NAFLD patients. These results suggest that RXRα acetylation is required for regulating the PPARα-mediated repression of PCSK9 transcription in the liver, and impaired RXRα acetylation in the NAFLD liver results in increased PCSK9 and atherosclerosis risk.