# IDOL and dyslipidemia in cardiovascular diseases

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $773,938

## Abstract

ABSTRACT
Despite a significant reduction of major vascular events through the use of statins, cardiovascular disease
(CVD) continues to be the leading cause of death. New strategies to address the residual risks include
combination therapy of statins with ezetimibe or PCSK9 inhibition. Recent clinical findings indicate that,
although effective in further reducing LDL-C, combination therapies do not proportionally translate in reduction
of CV events, likely from the relatively high plasma triglycerides still present. Furthermore, some patients
cannot reach the low LDL-C target levels or are drug intolerant and TG treatment is difficult. These challenges
highlight the need for new targets for intervention and novel therapeutic approaches for dyslipidemia. In vitro
and in mice models, IDOL was identified as an E3 ubiquitin ligase targeting LDLR, VLDLR and ApoER2 for
degradation and regulating plasma lipid homeostasis independently of PCSK9. Furthermore, in genetic
epidemiology studies IDOL was highly associated with LDL-C and CVD outcomes and loss-of-function alleles
result in extremely low LDL-C and reduced CVD risk. Unfortunately, intrinsic differences in IDOL biology
between mice and primates, create the need to develop an animal model that better approximates human
IDOL biology in order to advance IDOL research into the translational arena. Our preliminary studies indicate
that rabbits constitute a better model to test the feasibility of IDOL as a clinically relevant target for
hyperlipidemia and CVD. Indeed, unlike in mice, rabbit IDOL is induced in the liver in response to LXR
agonists, same as in monkeys and humans. IDOL knock-out rabbits have decreased LDL-C and upon high fat
high cholesterol diet, maintain low total cholesterol and low triglycerides. We will test the hypothesis that
reduced IDOL protein expression levels or activity -through gene deficiency or small molecule inhibitors- will
increase plasma lipid clearance, reduce hypercholesterolemia, hypertriglyceridemia and inflammation, resulting
in reduced atherosclerosis. Using IDOL knock-out, heterozygous and wild type rabbits, we will establish IDOL
as a therapeutic target for reducing atherosclerosis in Aim 1, to study IDOL contribution to liver-mediated
plasma lipid clearance, diet-induced atherosclerosis in aorta and coronary artery and the effects of newly
developed small molecule IDOL inhibitors. In Aim 2, we will deepen the characterization of IDOL KO effects of
the physiology of lipid handling and using primary rabbit cells we will define IDOL-dependent mechanisms in
hepatocytes underlying lipid clearance and the response in vitro to novel IDOL inhibitors. Human iPSC-derived
hepatocytes and macrophages combined with gain- and loss-of-function will address conservation of the
mechanisms across species. Completion of these aims by leveraging new IDOL rabbit models to overcome
the current barriers to advance IDOL translational research will provide compelling evidences and new f...

## Key facts

- **NIH application ID:** 9963349
- **Project number:** 5R01HL147527-02
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** YUQING Eugene CHEN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $773,938
- **Award type:** 5
- **Project period:** 2019-09-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9963349

## Citation

> US National Institutes of Health, RePORTER application 9963349, IDOL and dyslipidemia in cardiovascular diseases (5R01HL147527-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9963349. Licensed CC0.

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