Role of Retinoid X Receptor Alpha in regulating PCSK9 transcription in the liver

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PROJECT SUMMARY Cardiovascular disease (CVD) still is the leading cause of death in the United States. The demand for novel treatments lead to the recent discovery of 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. Many treatments targeting PCSK9 have been developed but have limited efficacy in lowing LDL- C. This proposal fills the critical knowledge gap by challenging the underlying presumption that RXRα is essential to regulate the transcription of PCSK9 in the liver of nonalcoholic fatty liver diseases (NAFLD) patients. RXRα is the core nuclear receptor, which always is considered to constitutively forms heterodimerization with other nuclear receptors. Our preliminary data showed that hepatic depletion of RXRα leads to hepatic lipid accumulation and PCSK9 induction, which can be abolished by AAV8-mediated hepatic overexpression of RXRα. Consistently, we observed the increased cholesterol and LDL-C in the plasma of RXRα hepatocyte-specific knockout (hepKO) mice, and hepatic overexpression of RXRα can significantly reduce the plasma cholesterol and LDL-C levels. These preliminary data bring two scientific questions needed to be determined in this proposal: 1) why RXRα deficiency has primary effects on the PPARα signaling pathway; 2) how RXRα regulates PCSK9 expression in the liver. To find answers, we focus on elucidating the effects of RXRα protein post-translational modification (PTM) on managing the partnership with PPARα and regulating PCSK9. Recently, we identified a previously unrecognized acetylation residue of RXRα, which controls the heterodimerization between RXRα and PPARα. The inhibitory effects of RXRα constitutively acetylated mutant further indicate that acetylation of RXRα is essential for preventing the induction of PCSK9 in the liver of RXRα hepKO mice. Our data are the first to show that RXRα is acetylated by CBP, and TNFα, the inflammatory cytokine presented in the NALFD liver, impairs the CBP-mediated acetylation of RXRα. 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 a central hypothesis that RXRα acetylation is required for regulating the PPARα-mediated transcription of PCSK9 in the liver, and impaired RXRα acetylation in the NAFLD liver results in the increased cholesterol and LDL-C. We will test this hypothesis with the following two aims: Aim 1: Determine the molecular mechanism by which RXRα regulates the transcription of PCSK9 in the liver; Aim 2: Determine if and the extent to which RXRα acetylation is a resilience factor to prevent the induction of PCSK9 and cholesterol in the fatty liver. Successful completion of studies proposed in this proposal will identify the mechanisms by which acetylated RXRα coordinates with PPARα to regulate PCSK9 transcription and prevent obesity-promoted hypercholesterolemia. This identification will allow for the development of new alternative strategies for attenuating PCSK9 induction in the NAFLD liver, which will help mitigate CVD risk, an NIH's mission directive.