New York University

Role of Retinoid X Receptor Alpha in Regulating PCSK9 Transcription in the Liver - 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 Rxra Is Essential to Regulate the Transcription of PCSK9 in the Liver of Nonalcoholic Fatty Liver Diseases (NAFLD) Patients. Rxra 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 Rxra Leads to Hepatic Lipid Accumulation and PCSK9 Induction, Which Can Be Abolished by AAV8-MEDIATED Hepatic Overexpression of Rxra. Consistently, We Observed the Increased Cholesterol and LDL-C in the Plasma of Rxra Hepatocyte-specific Knockout (HEPKO) Mice, and Hepatic Overexpression of Rxra 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 Rxra Deficiency Has Primary Effects on the Ppara Signaling Pathway; 2) How Rxra Regulates PCSK9 Expression in the Liver. to Find Answers, We Focus on Elucidating the Effects of Rxra Protein Post-translational Modification (PTM) on Managing the Partnership With Ppara and Regulating PCSK9. Recently, We Identified a Previously Unrecognized Acetylation Residue of Rxra, Which Controls the Heterodimerization Between Rxra and Ppara. the Inhibitory Effects of Rxra Constitutively Acetylated Mutant Further Indicate That Acetylation of Rxra Is Essential for Preventing the Induction of PCSK9 in the Liver of Rxra Hepko Mice. Our Data Are the First to Show That Rxra Is Acetylated by CBP, and Tnfa, the Inflammatory Cytokine Presented in the Nalfd Liver, Impairs the Cbp-mediated Acetylation of Rxra. Interestingly, We Also Observed the Decreased Acetylation of Rxra in the Liver of High-fat Diet (hfd)-fed Mice and Human Nafld Patients. These Results Suggest a Central Hypothesis That Rxra Acetylation Is Required for Regulating the Ppara-mediated Transcription of PCSK9 in the Liver, and Impaired Rxra 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 Rxra Regulates the Transcription of PCSK9 in the Liver; Aim 2: Determine If and the Extent to Which Rxra 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 Rxra Coordinates With Ppara 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.