# Role of Extracellular Long-Chain Acyl-carnitines in the Normal and Stressed Heart

> **NIH NIH F31** · JOHNS HOPKINS UNIVERSITY · 2024 · $32,974

## Abstract

PROJECT SUMMARY
Heart failure (HF) is a significant cause of cardiovascular-related death in the United States, with its incidence
increasing by over 40% when accompanied by obesity. The obese-HF phenotype is particularly common in HF
with a preserved ejection fraction, a major unmet medical need. The adverse interaction between obesity and
HF appears due, in part, to compromised myocardial metabolic fuel availability and flexibility. The heart's high
energy demand relies on ATP, mostly derived from FFA oxidation in mitochondria. Long chain fatty acids (LCFA),
which have over 12 carbons, are transported into mitochondria for beta oxidation through the acyl-carnitine cycle.
Our recent study found marked reductions in myocardial medium and long chain acyl-carnitines in human HF as
compared to controls, yet corresponding plasma levels were normal or elevated. This raises the question of
whether extracellular acylcarnitines (ex-ACs) can be taken up from plasma by the heart to be used for fuel, and
if in HF this process is diminished.
In new preliminary data, I now show there is lower expression of the plasma membrane LCFA transporters
(CD36, FATP3) and the protein needed to add carnitine to the FA (carnitine palmitoyltransferase 1b, CPT1b).
Whether this plays a key role in impeding ex-AC uptake by the myocytes or the heart, and the fate of any ex-AC
that is internalized is unknown. This project tests the hypothesis that ex-ACs are taken up and undergo beta-
oxidation by myocytes in vitro to contribute to ATP synthesis, O2 consumption, and CO2 generation. The studies
explore the fate of ex-ACs in cardiomyocytes and their utilization in both normal and stressed cells and hearts.
In Aim 1, I test the hypothesis that ex-ACs are taken up by cardiomyocytes via the critical membrane transporter
CD36, or if not, by another currently unknown transporter, and once taken up they undergo beta oxidation. These
studies utilize radiolabeled (14C) and heavy labeled (13C) palmitoyl-carnitine and oleoyl-carnitine, each contrasted
to their FFA form (palmitic acid and oleic acid) to determine cellular uptake and beta oxidation. The role of critical
transporters, carnitine modulators/recyclers are tested using pharmacological or genetic based loss of function
studies. In Aim 2, I explore the fate of ex-AC in vivo, comparing normal mice to those under acute and chronic
pressure overload via transverse aortic constriction (TAC). I will further examine the addition of a metabolic
stress induced by chronic high fat diet. To understand the uptake and processing in vivo, I will inject 13C labeled
acyl-carnitines into the bloodstream and measure organ specific uptake and downstream catabolic incorporation
of the labeled carbon (e.g into Krebs cycle intermediates). My goal is to understand the mechanisms and
metabolic consequences of ex-AC pertinent to cardiomyocyte metabolism, with the ultimate hope of enhancing
their use as fuel in heart failure. This research may provide insi...

## Key facts

- **NIH application ID:** 10995420
- **Project number:** 1F31HL176029-01
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Abigail S. Mulligan
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $32,974
- **Award type:** 1
- **Project period:** 2024-12-01 → 2027-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10995420

## Citation

> US National Institutes of Health, RePORTER application 10995420, Role of Extracellular Long-Chain Acyl-carnitines in the Normal and Stressed Heart (1F31HL176029-01). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/10995420. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*