Docosahexaenoic acid is both a product of and a precursor to tetracosahexaenoic acid in the rat

Abstract

Tetracosahexaenoic acid (THA; 24:6n-3) was first reported to be the immediate precursor to DHA in 1991 by Voss et al. (1), where n-3 docosapentaenoic acid (DPAn-3; 22:5n-3) had previously been thought to be directly converted to DHA via a 4-desaturation reaction. Later, a lack of labeled DHA accumulation in Zellweger's patients (2, 3) signaled a role for the peroxisomes in the -oxidation of THA to DHA, following the elongation and subsequent 6desaturation of DPAn-3 to n-3 tetracosapentaenoic acid (TPAn-3; 22:5n-3) and THA, respectively. Termed the "Sprecher pathway" (DPAn-3 → TPAn-3 → THA → DHA), this series of reactions have since been accepted as vital steps in the synthesis of DHA; however, recent evidence from human cells is contradictory and suggests that THA is a product, not a precursor, of DHA (4, 5). Currently, it appears possible that rats and humans synthesize DHA through different pathways; however, often-overlooked data from 1991 show elongation of DHA to THA in addition to the 6-desaturation TPAn-3 and -oxidation of THA to DHA (1). Furthermore, the human cell study demonstrated that in the absence of functional 6-desaturase activity, labeled DPAn-3 could be converted directly to DHA (5); however, it is possible that this 4-desaturase activity is upregulated in response to the absence of a 6desaturase enzyme. Recently, our laboratory demonstrated the sensitivity by GC/MS to determine daily synthesis-secretion rates for all n-6 and n-3 PUFAs following 3 h steady-state infusions of linoleic acid (18:2n-6) and -linolenic acid (ALA; 18:3n-3), respectively, in Long-Evans rats (6, 7). From these studies, we determined that the synthesis-secretion rates of THA and DHA from plasma unesterified ALA (7) and from plasma unesterified ALA and EPA in response to DHA Abstract Tetracosahexaeoic acid (THA; 24:6n-3) is thought to be the immediate precursor of DHA in rodents; however, the relationship between THA and DHA metabolism has not been assessed in vivo. Here, we infused unesterified 2 H 5-THA and 13 C 22-DHA, at a steady state, into two groups of male Long-Evans rats and determined the synthesis-secretion kinetics, including daily synthesis-secretion rates of all 20-24 carbon n-3 PUFAs. We determined that the synthesis-secretion coefficient (a measure of the capacity to synthesize a given fatty acid) for the synthesis of DHA from plasma unesterified THA to be 134-fold higher than for THA from DHA. However, when considering the significantly higher endogenous plasma unesterified DHA pool, the daily synthesis-secretion rates were only 7-fold higher for DHA synthesis from THA (96.3 ± 31.3 nmol/d) compared with that for THA synthesis from DHA (11.4 ± 4.1 nmol/d). Furthermore, plasma unesterified THA was converted to DHA and secreted into the plasma at a 2.5-fold faster rate than remaining as THA itself (26.2 ± 6.3 nmol/d), supporting THA's primary role as a precursor to DHA. In conclusion, using a 3 h infusion model in rats, we demonstrate for the first time in vivo that DHA is both a product and a precur...

Link between Omega 3 Fatty Acids Carried by Lipoproteins and Breast Cancer Severity

“…Regardless of the type of cancer considered, hormone-dependent or not, the youngest patients exhibited the most proliferative tumors, in agreement with the data in the literature. The % expression of Ki-67 allows researchers to define the proliferation index of the tumors [25], and its use in BC with a cut-off varying according to the authors from 1% to 28% [26]. In order to overcome the lack of consensus concerning this cut-off, we differentiated Ki-67 ≤ 20% as Prolif− and Ki-67 ≥ 30% as Prolif+.…”

Body surface area-based omega-3 fatty acids supplementation strongly correlates to blood concentrations in children.

“…However, some studies have indicated that the increase in EPA is not associated with retroconversion, but to inhibition of further transformation of EPA to DPA(-DHA) [44,45]. Results from a study in rats even suggest a transformation of DHA to THA [46]. In our study we did not detect THA, not even at the highest provided doses, suggesting that retroconversion [47] and/or feedback inhibition of EPA metabolism was predominating, explaining the unchanged DPA in the lower doses [48].…”

Tetracosahexaenoylethanolamide, a novel N-acylethanolamide, is elevated in ischemia and increases neuronal output

“…Future studies may be designed using intracerebroventricular injections of THEA to determine the half-life in the brain compared with other NAEs, such as DHEA. Alternatively, THA is rapidly converted to DHA in vivo (23), and if THEA synthesis is saturated, the excess unesterified THA in the brain could be used to synthesize additional DHA, and in turn DHEA. These are important molecules in neuroinflammation, as both unesterified DHA (40) and DHEA (41) are protective against lipopolysaccharide-induced neuroinflammation in rodent models.…”

“…Relative to the blood and other tissues, the brain has some of the highest levels of THA in the body (23,(25)(26)(27), and may therefore have added importance in neural tissues. In our animals, total brain THA was at least 20 nmol/g across all conditions and is substantially higher than previous reports of 1-6 nmol/ml THA in rodent plasma (23,26) and 1-3 nmol/ml in human plasma (42). This enrichment Fig.…”

“…in brain THA could be due to either a higher rate of uptake into the brain or an increase in synthesis from n-3 PUFA precursors such as EPA (20:5n-3) and/or DHA (23,31). To this point, cell lines originating from neural tissues, neuroblastoma (SK-N-SH) cells, and retinoblastoma (Y79) cells demonstrate strikingly different metabolism of DHA compared with cells originating from nonneuronal tissues, hepatocarcinoma (HepG2) cells, and breast cancer (MCF7) cells (24).…”