# Unraveling ApoE4 Promotion of Cardiometabolic Disease

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2021 · $568,956

## Abstract

Project Summary/Abstract
 Compared with individuals expressing the most common genetic variant of apolipoprotein E (apoE),
apoE3, those harboring apoE4 are at increased risk of both cardiovascular disease and type 2 diabetes
mellitus (T2DM). Although apoE classically participates in lipid transport, the basis for apoE4-associated risk
remains unclear, and there are no interventions available to break the link between apoE4 and vascular and
metabolic disorders. We recently discovered that the insulin resistance observed in mice expressing human
apoE4 is driven by skeletal muscle insulin resistance mediated by the apoE receptor apoER2 in endothelial
cells. Studies in culture showed that the underlying mechanism is apoE4-apoER2-induced inhibition of
endothelial cell insulin transport, which has a major impact on insulin action in muscle. In other recent work
we determined that thrombosis is markedly more severe in apoE4- versus apoE3-expressing mice. Cell
culture studies further indicated that this may be due to apoE4 promotion of von Willebrand factor (vWF)
secretion by endothelial cells. The Overall Goal of the proposed research is to elucidate how apoE4 actions
on endothelium influence glucose homeostasis and vascular disease pathogenesis. Aim 1 will determine how
apoE4 causes insulin resistance. A non-biased query of apoER2-interacting proteins and ensuing studies of
insulin transport in cultured endothelial cells suggest involvement of Dab2-interacting protein (DAB2IP) and
JIP1, which both modulate JNK signaling. Using endothelial cell-specific deletion in apoE3- and apoE4-
expressing mice, we will test the hypothesis that apoE4 promotes insulin resistance via endothelial apoER2
through DAB2IP- and JIP1-dependent mechanisms. Aim 2 will determine how apoE4 promotes
atherosclerosis and thrombosis. Studies of proteins interacting with apoER2 in endothelium and apoE4
enhancement of endothelial cell vWF secretion and monocyte adhesion indicate possible participation of the
protein phosphatase PP2A. In apoE3- and apoE4-expressing mice we will test the hypothesis that apoE4
promotes atherosclerosis and thrombosis via endothelial apoER2-related activation of PP2A. In Aims 1 and 2,
we will additionally use GWAS-based strategies to determine if the operative genes in mice are modifier
genes influencing apoE4-related risk of metabolic and vascular disease in humans. In Aim 3 we will devise
interventions against apoE4 and its mechanisms of action to preserve metabolic and vascular health. In
apoE4 mice the effect of JNK inhibition on insulin resistance and the effect of PP2A inhibition on
atherosclerosis and thrombosis will be evaluated. We will also use base editing to genetically correct apoE4
to apoE3 in vivo in the hepatocytes of apoE4 mice. Editing efficiency and impact on apoE4-related insulin
resistance, atherosclerosis and thrombosis will be evaluated. By accomplishing these Aims and unraveling
how apoE4 promotes cardiometabolic disease, it is expe...

## Key facts

- **NIH application ID:** 10192811
- **Project number:** 5R01HL144969-02
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** PHILIP W SHAUL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $568,956
- **Award type:** 5
- **Project period:** 2020-07-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10192811

## Citation

> US National Institutes of Health, RePORTER application 10192811, Unraveling ApoE4 Promotion of Cardiometabolic Disease (5R01HL144969-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10192811. Licensed CC0.

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