# Lipidated Amino Acids in Cardiometabolic Diseases

> **NIH NIH R01** · LOUISIANA STATE UNIV HSC SHREVEPORT · 2024 · $412,398

## Abstract

PROJECT SUMMARY/ABSTRACT
Non-alcoholic fatty liver disease (NAFLD) affects 25% of the global population at a substantial burden to the
health care system. Despite significant advances in our understanding of the underlying causes and considerable
efforts in drug development, no pharmacological therapy currently exists for this disease. Accelerated
atherosclerosis, independent of traditional risk factors, is the major cause of death in patients with NAFLD,
particularly in those with the more severe non-alcoholic steatohepatitis (NASH). Thus, there is an urgent clinical
need to identify new pathways for simultaneous targeting of NASH and atherosclerosis. Imbalanced lipid
metabolism and dysregulated amino acid metabolism are emerging as common features in both NASH and
atherosclerosis, although their crosstalk has not received much attention. Lipidated amino acids or N-acyl amino
acids (NAAs) have emerged as endogenous signaling molecules in which an amide bond links an amino acid to
the acyl moiety of a long-chain fatty acid. Yet, little is known about the metabolic regulation of NAAs, particularly
in cardiometabolic diseases. Our preliminary data uncovered that the liver is a major hub for NAA metabolism.
Unbiased transcriptomics revealed suppression of known NAA biosynthetic genes (GLYAT, ADH7 and PM20D1)
and upregulation of degradative genes (PAM, PTGS1 and PTGS2) in livers from humans and mice with NASH,
concomitant with marked reduction of NAAs, as determined by metabolomics. Hepatic NAAs inversely correlated
with NASH and inflammatory indices. Importantly, chronic administration of N-oleoyl leucine (C18:1-Leu), as
proof-of-concept, protected against diet-induced NASH, independent of changes in systemic energy metabolism.
This was associated with induction of hepatic peroxisome proliferator-activated receptor α (PPARα)/fatty acid
oxidation (FAO), suppression of C-C motif chemokine ligand 2 (CCL2) and reduced hepatic macrophages and
fibrosis. In atherosclerotic mice, C18:1-Leu reduced lesional macrophages and atherosclerosis, while
concurrently lowering hepatic steatosis and CCL2. Thus, our findings support the potential of NAAs for the
simultaneous treatment of NASH and atherosclerosis. This project will address the central hypothesis that lipid
overload and ensuing inflammation inhibit hepatic NAA formation, while NAAs stimulate hepatic PPARα and
suppress CCL2, simultaneously reducing NASH and atherosclerosis. Aim 1 will determine the mechanisms
driving suppression of NAAs in NASH and atherosclerosis using in vitro and in vivo models of loss- and gain-of-
function of NAA metabolic genes and will define genetic variants in these genes linking both diseases in GWAS
and human liver samples. Aim 2 will define NAAs as a potential therapy for NASH, thereby atherosclerosis, and
its dependence on PPARα-mediated hepatic FAO and suppression of CCL2 using new liver-specific and dietary
mouse models combined with in vitro approaches. This work will chara...

## Key facts

- **NIH application ID:** 10810710
- **Project number:** 5R01DK134011-03
- **Recipient organization:** LOUISIANA STATE UNIV HSC SHREVEPORT
- **Principal Investigator:** Oren Rom
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $412,398
- **Award type:** 5
- **Project period:** 2022-06-02 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10810710

## Citation

> US National Institutes of Health, RePORTER application 10810710, Lipidated Amino Acids in Cardiometabolic Diseases (5R01DK134011-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10810710. Licensed CC0.

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