# CSDE1 as a Post Transcriptional Regulator of the LDLR - Diversity Supplement

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2022 · $97,076

## Abstract

PROJECT SUMMARY/ABSTRACT OF PARENT GRANT
Low-density lipoprotein (LDL) is a key risk factor for atherosclerotic heart disease, the leading cause of death
in the US. Therapies that upregulate the hepatic LDLR lower LDL and protect against cardiovascular events.
Moreover, the LDLR also plays a fundamental role in maintenance of intracellular cholesterol homeostasis.
Therefore, the mechanisms that regulate the LDLR are important to understand. Via an innovative genome-
wide CRISPR interference screen, we identified CSDE1 as a novel post-transcriptional modulator of LDLR
mRNA stability. In tissue culture, knockdown of CSDE1 is as powerful as knockdown of the targets of statins or
PCSK9 inhibitors, the most effective LDL lowering therapies in the clinic. Moreover, CSDE1 also acts
independently of these targets. However, both the mechanism of and specificity for CSDE1’s effect on the
hepatic LDLR mRNA remain unknown. Therefore, the overall goal of this proposal is to establish the role of
CSDE1 as a specific regulator of the hepatic LDLR and circulating LDL. In Aim 1, we will establish the
mechanism by which hepatic CSDE1 regulates LDLR mRNA stability. Because CSDE1 binds the 3’ UTR of
LDLR, but its effects are tissue-dependent, we hypothesize that CSDE1 recruits other factors required for
LDLR mRNA decay. We will therefore establish the dynamic range of CSDE1’s effect through overexpression
studies, use mass spectrometry approaches to identify the additional protein components required for CSDE1-
mediated LDLR mRNA decay, and place CSDE1 in the context of a natural compound, berberine, which
affects LDLR mRNA stability through specific elements in the LDLR 3’ UTR. In Aim 2, we will identify the role of
hepatic CSDE1 in post-transcriptional regulation of the LDLR. We will use global translational profiling (RNA-
seq) to evaluate the effects of CSDE1 knockdown and overexpression on the hepatic transcriptome. We will
combine this with cross-linking and immunoprecipitation (CLIP) studies to identify the direct RNA interactors,
and their binding motifs, of hepatic CSDE1. In Aim 3, we will establish whether the effect of hepatic CSDE1
persists in vivo. We will use a mouse model to evaluate the effect of Csde1 knockdown and overexpression on
plasma lipids and in vivo hepatic Ldlr regulation. Together, this project will identify the mechanism and fidelity
of a promising new regulator of the LDLR, an extremely important player in the development of atherosclerosis.
The results will establish CSDE1 as a promising therapeutic target. Moreover, they will provide insight into the
mechanism of specificity of a general mechanism of mRNA regulation, with implications for fundamental cell
biology and other disease states.

## Key facts

- **NIH application ID:** 10635281
- **Project number:** 3R01HL159457-02S1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** John S Chorba
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $97,076
- **Award type:** 3
- **Project period:** 2022-08-19 → 2022-08-20

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10635281

## Citation

> US National Institutes of Health, RePORTER application 10635281, CSDE1 as a Post Transcriptional Regulator of the LDLR - Diversity Supplement (3R01HL159457-02S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10635281. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*