# Regulation of Endothelial Lipid Metabolism in the Setting of Diabetes and Critical Limb Ischemia to Prevent Surgical Complications

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2022 · $525,499

## Abstract

PROJECT ABSTRACT
Background & Significance: Peripheral arterial disease (PAD) affects 12 million people in the US (1 in 27
individuals). Individuals with diabetes are nearly 10 times more likely to develop end-stage surgical
complications such as critical limb ischemia (CLI) and major lower extremity amputation. This leads to
significant health, psychological, and financial burdens on surgical patients with diabetes. Therefore, it is
paramount to better understand this chronic disease process in order to develop more effective treatment
strategies, and improve the health of these patients.
 Fenofibrate, a peroxisome proliferator activated receptor alpha (PPARα) agonist that lowers serum
triglycerides, is the only medication to date shown to reduce peripheral amputation rates in patients with
diabetes. However, it is unknown how Fenofibrate confers this benefit, and therefore it is seldom used in the
clinical management of surgical patients with diabetes and CLI who are at risk of amputation.
 De novo lipogenesis is a multi-step lipid synthesis pathway that is known to contribute to the pathogenesis
of diabetes in non-vascular organ tissue, and is regulated by fatty acid synthase (FAS) and
choline/ethanolamine phosphotransferase-1 (CEPT1). Interplay between these enzymes can lead to activation
of PPARα-mediated signaling. It is unknown whether Fenofibrate can impact de novo lipogenesis, endothelial
cell (EC) lipid metabolism, and peripheral arterial atheroprogression in the setting of diabetes.
Preliminary Data: We observed that Fenofibrate can indeed affect peripheral limb perfusion in the setting of
altered de novo lipogenesis. We also observed that both CEPT1 and FAS are abundant in the peripheral
arterial intima of patients with diabetes and CLI. Additionally, we recently discovered that serum circulating
FAS (cFAS) is elevated in the serum of patients with advanced diabetes and CLI. Furthermore, cept1 knockout
in the endothelium leads to significantly reduced atheroprogression and normalization of serum lipid profiles.
Innovation: The main objective of this proposal is to determine whether de novo lipogenesis and Fenofibrate
can affect peripheral atheroprogression in the setting of diabetes. This line of investigation will be highly
innovative since it will address key knowledge gaps in the mechanisms that contribute to peripheral
atheroprogression in diabetes, and may help tailor therapy for surgical patients afflicted by this condition.
Specific Aims: We hypothesize that CEPT1 and cFAS are key players in EC lipid metabolism and have
important roles in peripheral arterial atheroprogression in the setting of diabetes and CLI. Using a complement
of biochemical techniques and already generated mouse lines, we will test this hypothesis in two aims: Aim 1
will determine whether CEPT1 and cFAS can affect peripheral arterial atheroprogression in the setting of
diabetes, and Aim 2 will determine whether Fenofibrate affects endothelial de novo lipoge...

## Key facts

- **NIH application ID:** 10375540
- **Project number:** 5R01HL153262-02
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Mohamed A. Zayed
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $525,499
- **Award type:** 5
- **Project period:** 2021-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10375540

## Citation

> US National Institutes of Health, RePORTER application 10375540, Regulation of Endothelial Lipid Metabolism in the Setting of Diabetes and Critical Limb Ischemia to Prevent Surgical Complications (5R01HL153262-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10375540. Licensed CC0.

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