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

Abstract

Dietary odd-chain saturated fatty acids (OCFAs) are present in trace levels in dairy fat and some fish and plants. Higher circulating concentrations of OCFAs, pentadecanoic acid (C15:0) and heptadecanoic acid (C17:0), are associated with lower risks of cardiometabolic diseases, and higher dietary intake of OCFAs is associated with lower mortality. Population-wide circulating OCFA levels, however, have been declining over recent years. Here, we show C15:0 as an active dietary fatty acid that attenuates inflammation, anemia, dyslipidemia, and fibrosis in vivo, potentially by binding to key metabolic regulators and repairing mitochondrial function. This is the first demonstration of C15:0's direct role in attenuating multiple comorbidities using relevant physiological mechanisms at established circulating concentrations. Pairing our findings with evidence that (1) C15:0 is not readily made endogenously, (2) lower C15:0 dietary intake and blood concentrations are associated with higher mortality and a poorer physiological state, and (3) C15:0 has demonstrated activities and efficacy that parallel associated health benefits in humans, we propose C15:0 as a potential essential fatty acid. Further studies are needed to evaluate the potential impact of decades of reduced intake of OCFA-containing foods as contributors to C15:0 deficiencies and susceptibilities to chronic disease.

Conflict of interest statement

S.V. is a co-founder of and employed by Epitracker, Inc and Seraphina Therapeutics, Inc, which financed studies in this paper and hold exclusive licensing rights from the U.S. Navy to commercialize odd-chain saturated fatty acids as human and animal health products. R. Lumpkin’s work related to this study was also financed by Epitracker. E.A. Dennis is a member of the Scientific Advisory Board of Epitracker and holds equity.

Figures

Figure 1

Reduced mitochondrial reactive oxygen species production in stressed human cell systems supplemented with C15:0 at 10, 20 and 50 µM compared to non-supplemented controls. Endpoint of upper whisker, maximum; upper edge of box, 75th percentile; line inside box, median; diamond, mean; lower edge of box, 25th percentile; endpoint of lower whisker, minimum; circle, outlier.

Figure 2

Annotated dose-dependent anti-inflammatory and antifibrotic activities of C15:0 (0.74, 2.2, 6.7 and 20 µM) in primary human cell systems mimicking inflammation and fibrosis. MCP-1 = monocyte chemoattractant protein 1, sIgG = secreted immunoglobulin G, PAI-1 = plasminogen activation inhibitor 1.

Figure 3

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. MCP-1 = monocyte chemoattractant protein 1; IgG = immunoglobulin G; IL-17A, IL-17F, IL-6 = interleukin 17 A, 17 F and 6; sTNFα = secreted tumor necrosis factor alpha; VCAM-1=vascular adhesion molecule 1, CXCL10, CXLX11, CXCL9 = chemokine ligand 10, 11 and 9; PAI-1 = plasminogen activation inhibitor 1). BT System = Primary human cell system in Eurofins/DiscoverX BioMAP Diversity PLUS panel modeling T cell dependent B cell proliferation; HDF3CGF System = Primary human cell system in Eurofins/DiscoverX BioMAP Diversity PLUS panel modeling matrix/tissue remodeling in the context of Th1-type inflammation, including fibrosis and chronic inflammation.

Figure 4

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). Upper edge of box, maximum; line inside box, median; diamond, mean; lower edge of box, minimum.

Figure 5

Comparisons of circulating concentrations of the pro-inflammatory chemokine, monocyte chemoattractant 1 (MCP-1) (a), pro-inflammatory cytokine, interleukin 6 (IL-6) (b), glucose (c), and total cholesterol (d) between high fat diet-induced obese in vivo model supplemented with low dose daily oral C15:0 (pentadecanoic acid, 5 mg/kg) over 12 weeks and non-supplemented controls. Wilcoxon two-sided p values.

Figure 6

Comparisons of red blood cell indices, including hemoglobin (a), red blood cell counts (b), red blood cell distribution width (c), and reticulocytes (d) between high fat-diet fed in vivo models for nonalcoholic steatohepatitis (NASH) supplemented with higher doses of daily oral C15:0 (pentadecanoic acid, 35 mg/kg) over 11 weeks and non-supplemented controls. Wilcoxon two-sided p values.

Figure 7

Comparisons of circulating globulins (a), platelets (b), cholesterol (c), and triglycerides (d) between high fat-diet fed in vivo models for nonalcoholic steatohepatitis (NASH) supplemented with higher doses of daily oral C15:0 (pentadecanoic acid, 35 mg/kg) over 11 weeks and non-supplemented controls. Wilcoxon two-sided p values.