# Contribution of novel lysoplasmalogenases enzymes in regulating macrophage immunometabolic responses in cardiovascular disease

> **NIH NIH R01** · YALE UNIVERSITY · 2024 · $773,997

## Abstract

PROJECT SUMMARY
 Alterations in the control of lipid homeostasis can lead to cardiometabolic diseases, including
atherosclerosis, the most common cause of mortality in Western societies.
 Our previous studies have demonstrated the importance of miRNAs in regulating high-density
lipoprotein (HDL)-C and LDL-C. Work from our group and others identified miR-33a/b as key regulators of
cellular cholesterol efflux and uptake, HDL biogenesis and fatty acid metabolism. Notably, we have recently
discovered that miR-33 and the nuclear receptor liver X receptor (LXR) regulates the expression of
transmembrane protein 86a (TMEM86a), which is a lysoplasmalogenase that regulates plasmalogen
(phospholipid) metabolism. This finding is highly relevant given the key role of these phospholipids as
reservoir of polyunsaturated fatty acids, which are the precursors of bioactive lipids that control inflammation
resolution. Plasmalogen/lysoplasmalogen content in cells can also regulate membrane fluidity, which may
contribute to cytokine-mediated inflammatory responses, efferocytotic capacity, ER stress, lipid
peroxidation, and cellular cholesterol efflux in macrophages. Notably, TMEM86a is highly expressed in
human and mouse atherosclerotic lesions, suggesting a relevant role for this enzyme in regulating
macrophage immunometabolic response during atherosclerosis.
 Together, these novel findings strongly suggest that LXR/miR-33/TMEM86a signalling pathway
might contribute to the chronic vascular inflammation observed in atherosclerotic lesions. To investigate the
functional relevance of TMEM86a in regulating macrophage phospholipid metabolism during the
progression of atherosclerosis, we have recently generated a mouse model that lack the expression of
TMEM86a in macrophages. Using these mice and cutting-edge techniques (genomics and metabolomics),
we will elucidate the contribution of LXR/miR-33/TMEM86a pathway in atherogenesis.

## Key facts

- **NIH application ID:** 10981457
- **Project number:** 1R01HL171480-01A1
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Carlos Fernandez Hernando
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $773,997
- **Award type:** 1
- **Project period:** 2024-06-01 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10981457

## Citation

> US National Institutes of Health, RePORTER application 10981457, Contribution of novel lysoplasmalogenases enzymes in regulating macrophage immunometabolic responses in cardiovascular disease (1R01HL171480-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10981457. Licensed CC0.

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