Pentadecanoic Acid Shows Anti-Inflammatory and PPAR-Activating Properties in Preclinical Models

Title: Efficacy of dietary odd-chain saturated fatty acid pentadecanoic acid parallels broad associated health benefits in humans: could it be essential

Journal: Scientific reports

Published: 2020

Background

The study focuses on pentadecanoic acid (C15:0), a saturated fatty acid, hypothesized to act as a ligand for peroxisome proliferator-activated receptors (PPARs) and potentially possess anti-inflammatory and antifibrotic properties. This hypothesis was based on its structural similarity to other known PPAR ligands and its potential benefits in cellular systems related to inflammation and fibrosis.

Materials & Methods

Free Fatty Acids

Synthetic saturated fatty acids, including pentadecanoic acid (C15:0) and heptadecanoic acid (C17:0), were sourced from Millipore Sigma and used in the studies.

Lipidomic Analysis

Lipidomic profiling was performed using liquid chromatography coupled with mass spectrometry (LC-MS) to characterize changes in lipid composition induced by C15:0 treatment. Lipid extracts from treated cells and tissues were analyzed to identify alterations in lipid species and pathways affected by C15:0.

Pharmacokinetics Study

A 24-hour pharmacokinetic study in Sprague Dawley rats administered C15:0 orally determined serum concentrations using deuterated forms of C15:0 and C17:0, analyzed by capillary gas chromatography/mass spectrometry.

14-day Toxicology Study

Sprague Dawley rats were orally dosed with C15:0 daily for 14 days to evaluate safety at varying doses. Clinical observations, body weight measurements, clinical chemistries, and organ histopathology were assessed.

Oral Supplement Studies

In vivo studies using high-fat diet-induced obesity models in mice and non-alcoholic steatohepatitis (NASH) models in rabbits investigated the effects of oral C15:0 supplementation on metabolic indices, inflammatory biomarkers, liver histology, and blood-based variables.

Results

PPAR Agonist Activity

The cell-based assays demonstrated that C15:0 significantly activated PPARα, PPARδ, and PPARγ receptors in a dose-dependent manner (Figure 1). Compared to controls and reference agonists, C15:0 exhibited robust agonist activity across all PPAR isoforms, particularly notable in PPARα and PPARγ activation assays. These findings suggest potent regulatory effects of C15:0 on lipid metabolism and inflammatory pathways mediated by PPAR signaling.

Mitochondrial ROS Production

Treatment with C15:0 resulted in a dose-dependent reduction in mitochondrial reactive oxygen species (ROS) production in HepG2 cells (Figure 2). The MitoSOX Red assay showed significant decreases in ROS levels compared to untreated controls, indicating potential antioxidant properties of C15:0, crucial for mitigating oxidative stress in metabolic disorders.

Lipidomic Profiling

Lipidomic analysis revealed distinct alterations in lipid composition upon C15:0 treatment. LC-MS identified significant changes in specific lipid species, including increased levels of phospholipids and decreased triglycerides in treated samples compared to controls (Figure 3). These findings suggest a regulatory role of C15:0 in lipid metabolism pathways, influencing cellular membrane dynamics and metabolic homeostasis.

Annotated dose-dependent anti-inflammatory and antifibrotic activities of saturated fatty acids (C13:0, C14:0, C15:0, and C16:0 in 20 µM) in primary human cell systems mimicking inflammation and fibrosis.

Pharmacokinetics and Safety

Pharmacokinetic studies demonstrated rapid absorption and distribution of C15:0 in rat serum following oral administration. Peak concentrations were observed within 2 hours, with a steady decline over 24 hours (Figure 4). Toxicology assessments over 14 days indicated no significant adverse effects on clinical observations, body weight, or organ histopathology, affirming the safety profile of C15:0 at therapeutic doses.

Plasma deuterated C15:0 (a), C17:0 (b), and C13:0 (c) concentrations achieved over 24 h in male Sprague Dawley rats (n = 6 total, 3 per time point between 15 min and 12 h) dosed orally once with deuterated C15:0 (35 mg/kg body weight).

Reference

Liu, Ran, et al. "Determination of polyamine metabolome in plasma and urine by ultrahigh performance liquid chromatography–tandem mass spectrometry method: Application to identify potential markers for human hepatic cancer." Analytica chimica acta 791 (2013): 36-45. http://dx.doi.org/10.1016/j.aca.2013.06.044

* For Research Use Only. Not for use in diagnostic procedures.

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