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

> **NIH NIH R01** · NEW YORK UNIVERSITY D/B/A NYU LONG ISLAND SCHOOL OF MEDICINE · 2024 · $599,835

## Abstract

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 prev...

## Key facts

- **NIH application ID:** 10814148
- **Project number:** 5R01DK135630-02
- **Recipient organization:** NEW YORK UNIVERSITY D/B/A NYU LONG ISLAND SCHOOL OF MEDICINE
- **Principal Investigator:** QING MIAO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $599,835
- **Award type:** 5
- **Project period:** 2023-04-01 → 2027-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10814148

## Citation

> US National Institutes of Health, RePORTER application 10814148, Role of Retinoid X Receptor Alpha in regulating PCSK9 transcription in the liver (5R01DK135630-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10814148. Licensed CC0.

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