# Molecular Regulation of LDL Receptor Expression

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $625,479

## Abstract

PROJECT SUMMARY
 The expression level of the LDL receptor (LDLR) in the liver is a major determinant of an individual’s
lifetime risk of atherosclerotic cardiovascular disease (ASCVD). Although SREBP signaling plays an important
role in LDLR gene regulation, it is highly likely that other transcription factors bind to noncoding cis-regulatory
elements to further modulate LDLR expression. In particular, several common genetic variants within a ~20 kb
interval near the LDLR transcription start site are each strongly associated with LDL cholesterol and ASCVD
risk in human genome-wide association studies. Since many of these variants are co-inherited, however, it is
unclear which are causal for an alteration in LDLR gene expression. In preliminary studies, we have performed
a high-throughput CRISPR screen that revealed a strong functional influence on LDLR expression for a ~0.6
kb region within the first intron of LDLR, with minimal effect observed for the remainder of the ~20 kb GWAS-
associated interval. This region furthermore exhibits biochemical features of enhancer activity, an enrichment
in transcription factor binding motifs, and a high degree of evolutionary conservation among vertebrates. In this
proposal, we seek to build upon this discovery to test our central hypothesis that an enhancer in the first intron
of LDLR modulates its expression and the risk of ASCVD. In Aim 1, we will fine map the activity of the LDLR
enhancer and identify the transcription factors that govern its effect. In Aim 2, we will generate mice with
deletion of the first intronic Ldlr enhancer or its replacement with the homologous human sequence to establish
its physiologic significance to lipoprotein metabolism in vivo. In Aim 3, we will engineer a synthetic version of
the LDLR enhancer with optimized activity as a potential target for therapeutic genome editing. Together this
work will clarify the fundamental biology of LDLR gene regulation and lay the groundwork for the long-term
development of a novel genome editing strategy to prevent and treat ASCVD.

## Key facts

- **NIH application ID:** 10796478
- **Project number:** 1R01HL167733-01A1
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Brian T Emmer
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $625,479
- **Award type:** 1
- **Project period:** 2024-01-01 → 2028-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10796478

## Citation

> US National Institutes of Health, RePORTER application 10796478, Molecular Regulation of LDL Receptor Expression (1R01HL167733-01A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10796478. Licensed CC0.

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