# Targeting Scap to Lower ApoB-Containing Lipoproteins (ApoBCL) Production

> **NIH NIH P01** · UT SOUTHWESTERN MEDICAL CENTER · 2024 · $487,080

## Abstract

Elevated plasma levels of triglyceride-rich ApoBCLs (ApoB-Containing Lipoproteins) constitute a major
component of the residual risk for coronary heart disease (CHD) in patients who have been treated with statins
and/or PCSK9 inhibitors. To mitigate the ApoBCL risk component, we need a deeper understanding of the
machinery that controls the production of ApoBCLs. This machinery is comprised of two membrane proteins,
Scap and Sterol Regulatory Element-Binding Proteins (SREBPs). Scap is a protein embedded in the
endoplasmic reticulum (ER) membrane through eight transmembrane helices. Scap forms complexes with
SREBPs, which are also bound to the ER membrane through two transmembrane helices. SREBPs contain
transcription factor domains that control the synthesis of fatty acids, triglycerides, and cholesterol, which form
the lipid component of ApoBCLs. Activation of SREBPs requires their transport by Scap to the Golgi where two
proteases release their transcription factor domain that can now enter the nucleus for target gene activation.
When cholesterol in the ER rises and binds to Scap, it traps SREBPs in the ER, thus preventing proteolytic
cleavage and nuclear entry. A major hurdle in understanding Scap’s switch-like molecular mechanism and how
it controls SREBPs and ApoBCL production is the lack of a soluble cholesterol-mimetic compound that
specifically binds and inhibits Scap.
 This proposal is based on a recent breakthrough in our laboratory involving the development of a novel high-
throughput and rapid screening protocol, which has identified the first small molecule that binds specifically to
Scap’s cholesterol-binding site and blocks activation of SREBPs. Scap contains two large loops (Loop1 and
Loop7) that extend into the lumen of the ER bind each other when cholesterol in the ER is low. When ER
cholesterol rises, it binds to Loop1, causing Loop1 to dissociate from Loop7, trapping the Scap/SREBP complex
in the ER and blocking the transcriptional activation of all SREBP target genes. In Aim 1, we outline studies to
improve the potency of our recently discovered cholesterol-mimetic Scap inhibitor and will use these inhibitors
to understand how Loop1 dissociates from Loop7. The inhibitors will also be used as stabilizing agents to enable
structural determination of Scap, which will elucidate the cholesterol binding mechanism at an atomic level. In
Aim 2, we outline our approach to optimizing the in vivo pharmacokinetic properties of our various Scap
inhibitors, after which we will explore their effects in inhibiting Scap and SREBP target genes in livers of mice
under different metabolic conditions. Our previous studies involving genetically altered mice revealed that
inhibition of Scap in the liver blocks SREBPs and markedly reduces synthesis of fatty acids, triglycerides, and
cholesterol, dramatically lowering ApoBCL production in these models and also in wild-type mice fed a high fat
diet and in hamsters fed a high carbohydrate diet. If thes...

## Key facts

- **NIH application ID:** 10755255
- **Project number:** 5P01HL160487-03
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Arun Radhakrishnan
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $487,080
- **Award type:** 5
- **Project period:** 2022-01-01 → 2026-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10755255

## Citation

> US National Institutes of Health, RePORTER application 10755255, Targeting Scap to Lower ApoB-Containing Lipoproteins (ApoBCL) Production (5P01HL160487-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10755255. Licensed CC0.

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