# Novel Transcriptional & Post-Transcriptional Regulators of Endothelial Metabolism in Atherosclerosis

> **NIH NIH F31** · YALE UNIVERSITY · 2023 · $47,694

## Abstract

PROJECT SUMMARY
The progression of cardiovascular disease has only recently been noted to involve changes in endothelial (EC)
metabolism. Atherosclerosis, a disease of vascular lipid accumulation and inflammation, is linked to a
metabolic switch of the endothelium. However, the regulation of this switch is incompletely defined. Small non-
coding microRNAs have recently been identified as regulators of inflammation and metabolism. For example,
microRNA-33 (miR-33) has been extensively implicated in lipid metabolism, yet its precise role in ECs is
unknown. Another master regulator of lipid metabolism, whose role in ECs is yet to be defined, is Liver X
Receptor (LXR). This proposal seeks to determine how endothelial-specific miR-33 and LXR regulate EC
metabolism and determine if their disruption affects atherosclerotic progression. miR-33 attenuates the
removal of cholesterol from cells while on the other hand LXR signaling promotes this process. Since
cholesterol retention is implicated in atherogenic processes in the endothelium, this suggests a pro-
atherogenic role for endothelial miR-33 and an anti-atherogenic role for endothelial LXR signaling. Additionally,
other miR-33 targets include enzymes in fatty acid oxidation (FAO). Since dampened FAO promotes
atherogenic EC processes such as the Endothelial to Mesenchymal Transition, this emphasizes another pro-
atherogenic role of miR-33. Notably, there are several points of possible crosstalk between miR-33 and LXR
signaling – namely that LXR can potentially regulate miR-33 expression and that the miR-33 targets include
LXR-induced genes – suggesting an interplay between their effects on metabolism. Therefore, the central
hypothesis is that miR-33 and LXRs operate in complementary fashions to maintain cholesterol and lipid
homeostasis in ECs, and that disruption of either of their signaling perpetuates atherosclerosis. This
hypothesis will be tested by addressing the following specific aims: 1) Investigate the role of miR-33 in
modulating EC lipid metabolism and atherosclerosis; 2) Delineate the contribution of LXR signaling to EC
metabolism and dysfunction in atherosclerosis. The use of novel mouse models with endothelial-specific
deletion of miR-33 or the LXRs will provide key insight into their role in atherogenesis. These aims will then be
further tested in vitro with a combination of state-of-the-art approaches upon miR-33 or LXR gain- or loss-of-
function to determine their regulation of EC metabolism. The proposed research is significant because it is
expected to identify two critical cell-autonomous regulators of endothelial metabolism and atherosclerosis.
Long-term, the goal of this project is to deepen our understanding of the regulation of EC metabolism and
identify novel regulators that can be therapeutically targeted in cardiovascular disease.

## Key facts

- **NIH application ID:** 10683705
- **Project number:** 5F31HL156319-02
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Kathryn Citrin
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $47,694
- **Award type:** 5
- **Project period:** 2022-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10683705

## Citation

> US National Institutes of Health, RePORTER application 10683705, Novel Transcriptional & Post-Transcriptional Regulators of Endothelial Metabolism in Atherosclerosis (5F31HL156319-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10683705. Licensed CC0.

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