Metabolic fate of docosahexaenoic acid (DHA; 22:6n‐3) in human cells: direct retroconversion of DHA to eicosapentaenoic acid (20:5n‐3) dominates over elongation to tetracosahexaenoic acid (24:6n‐3)

Abstract

Docosahexaenoic acid (22:6n-3) supplementation in humans causes eicosapentaenoic acid (20:5n-3) levels to rise in plasma, but not in neural tissue where 22:6n-3 is the major omega-3 in phospholipids. We determined whether neuronal cells (Y79 and SK-N-SH) metabolize 22:6n-3 differently from non-neuronal cells (MCF7 and HepG2). We observed that 13C-labeled 22:6n-3 was primarily esterified into cell lipids. We also observed that retroconversion of 22:6n-3 to 20:5n-3 was 5- to 6-fold greater in non-neural compared to neural cells and that retroconversion predominated over elongation to tetracosahexaenoic acid (24:6n-3) by 2- to 5-fold. The putative metabolic intermediates, 13C-labeled 22:5n-3 and 13C-labeled 24:5n-3, were not detected in our assays. Analysis of the expression of enzymes involved in fatty acid beta-oxidation revealed that MCF7 cells abundantly expressed the mitochondrial enzymes CPT1A, ECI1, and DECR1, whereas the peroxisomal enzyme ACOX1 was abundant in HepG2 cells, thus suggesting that the initial site of 22:6n-3 oxidation depends on the cell type. Our data reveal that non-neural cells more actively metabolize 22:6n-3 to 20:5n-3 via channeled retroconversion, while neural cells retain 22:6n-3.

2-Hydroxy-Docosahexaenoic Acid Is Converted Into Heneicosapentaenoic Acid via α-Oxidation: Implications for Alzheimer’s Disease Therapy

“…The preferential metabolic route for DHA must be β-oxidation, although other metabolic transformations cannot be ruled out. In fact, DHA can be converted into EPA (eicosapentaenoic acid, C20:5 n-3) (Park et al, 2016) and indeed, we detected a significant increase in EPA after DHA stimulation (see Table 2). Likewise, there was a similar upregulation of docosapentaenoic acid (DPA, C22:5 n-3) following DHA stimulation (see Table 2), suggesting that DHA could be converted into DPA.…”

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

“…It is possible that the n-3 PUFA biosynthetic pathway behaves very differently in isolated liver microsomes or hepatocytes compared with in living mammals. In such a scenario, DPAn-3 could be desaturated directly to DHA by a 4-desaturase as evidenced in human cells (4,5), further elongated to THA, and then quickly -oxidized back to DHA in the peroxisome. Interestingly, cells grown in the presence of labeled DHA demonstrated an up to 5-fold higher retroconversion of DHA to EPA compared with elongation to THA (4).…”

“…Furthermore, although synthesis secretion of DHA from THA is significantly higher than THA from DHA, additional studies feeding DHA would be expected to yield more similar rates between the directions. In addition, the recent application of these infusion models to humans (24), the evidence from human cell lines suggesting the bypassing of the Sprecher pathway (4,5), and the potentially very low 2 H 5 -THA tracer requirements make the implementation of human THA infusions an exciting future step. In particular, the comparison of DHA synthesis rates between individuals with peroxisomal disorders, such as Zellweger's syndrome, would lead to an even more comprehensive understanding of such conditions.…”

Docosahexaenoic acid, 22:6n‐3: Its roles in the structure and function of the brain

“…Retro‐conversion of DHA to EPA occurs in the peroxisomes via β‐oxidation to remove the double bond at position 4. Retro‐conversion of DHA is more common in non‐neural cells than neural cells (Park et al, 2016). However, recently it was shown that increased plasma level of EPA in human following DHA supplementation did not occur via retro‐conversion rather a result of slowed metabolism and/or accumulation of plasma EPA (Metherel et al, 2019).…”