Retinal bioavailability and functional effects of a synthetic very-long-chain polyunsaturated fatty acid in mice

Abstract

Rare, nondietary very-long-chain polyunsaturated fatty acids (VLC-PUFAs) are uniquely found in the retina and a few other vertebrate tissues. These special fatty acids play a clinically significant role in retinal degeneration and development, but their physiological and interventional research has been hampered because pure VLC-PUFAs are scarce. We hypothesize that if Stargardt-3 or age-related macular degeneration patients were to consume an adequate amount of VLC-PUFAs that could be directly used in the retina, it may be possible to bypass the steps of lipid elongation mediated by the retina’s ELOVL4 enzyme and to delay or prevent degeneration. We report the synthesis of a VLC-PUFA (32:6 n-3) in sufficient quantity to study its bioavailability and functional benefits in the mouse retina. We acutely and chronically gavage fed wild-type mice and Elovl4 rod–cone conditional knockout mice this synthetic VLC-PUFA to understand its bioavailability and its role in visual function. VLC-PUFA-fed wild-type and Elovl4 conditional knockout mice show a significant increase in retinal VLC-PUFA levels in comparison to controls. The VLC-PUFA-fed mice also had improvement in the animals’ visual acuity and electroretinography measurements. Further studies with synthetic VLC-PUFAs will continue to expand our understanding of the physiological roles of these unique retinal lipids, particularly with respect to their potential utility for the treatment and prevention of retinal degenerative diseases.

Dietary fish oil enriched in very-long-chain polyunsaturated fatty acid reduces cardiometabolic risk factors and improves retinal function

“…No other serum or retinal changes for the other measured fatty acids were observed over time, except for a small increase in retinal 28:4 levels at 24 h after dosing (p < 0.05 vs. baseline). Based on the rapid absorption of orally administered fish oil VLCPUFA concentrate, which agrees with previous observations where chemically synthesized C32:6 was used, 11 we euthanized mice following a light fasting (5 h) in the 8-week dietary study to capture the change in plasma levels of VLCPUFAs. Mice on VLCPUFA supplementation for 8 weeks showed higher levels of 24:5, 26:6, and 28:8 in the plasma, liver, brain, and eyes compared with control diet ( Figure 1 B and Table S3 ).…”

Dietary fish oil enriched in very-long-chain polyunsaturated fatty acid reduces cardiometabolic risk factors and improves retinal function

“…No other serum or retinal changes for the other measured fatty acids were observed over time, except for a small increase in retinal 28:4 levels at 24 h after dosing (p < 0.05 vs. baseline). Based on the rapid absorption of orally administered fish oil VLCPUFA concentrate, which agrees with previous observations where chemically synthesized C32:6 was used, 11 we euthanized mice following a light fasting (5 h) in the 8-week dietary study to capture the change in plasma levels of VLCPUFAs. Mice on VLCPUFA supplementation for 8 weeks showed higher levels of 24:5, 26:6, and 28:8 in the plasma, liver, brain, and eyes compared with control diet ( Figure 1 B and Table S3 ).…”

Novel Approaches for Elongation of Fish Oils into Very-Long-Chain Polyunsaturated Fatty Acids and Their Enzymatic Interesterification into Glycerolipids

“…Reaction schemes and calculations are shown in the Figures S4 and S5 . As shown in Table 3 , the three-step elongation reported herein allowed us a significant improvement of the AE (52.71%) and PAE (6.17%) compared to the synthesis of Goruspundi et al (ref ( 32 ))/Wade et al (ref ( 49 )), indicating that more DHA used as the starting material was transformed into final product C28:6 n -3. In the case of our study, E-Factor was reduced 2.5-fold compared to the one of Goruspundi et al (ref ( 32 ))/Wade et al (ref ( 49 )), creating a lower amount of waste as well as byproducts ( Table 3 ).…”

Genotoxicity evaluation of a fish oil concentrate containing Very Long Chain Fatty Acids

“…The peak plasma level as measured in this study was between 2 and 4 hrs. In a similar study, serum samples from WT mice fed a bolus of 6 mg/kg C36 VLCFA (C36:6 n-3) showed a peak uptake of C36 at 2 h with the majority of uptake being between 2 and 8 h after bolus feeding [11] .…”

Dietary fish oil enriched in very-long-chain polyunsaturated fatty acid reduces cardiometabolic risk factors and improves retinal function

“…No other serum or retinal changes for the other measured fatty acids were observed over time, except for a small increase in retinal 28:4 levels at 24 h after dosing (p < 0.05 vs. baseline). Based on the rapid absorption of orally administered fish oil VLCPUFA concentrate, which agrees with previous observations where chemically synthesized C32:6 was used, 11 we euthanized mice following a light fasting (5 h) in the 8-week dietary study to capture the change in plasma levels of VLCPUFAs. Mice on VLCPUFA supplementation for 8 weeks showed higher levels of 24:5, 26:6, and 28:8 in the plasma, liver, brain, and eyes compared with control diet ( Figure 1 B and Table S3 ).…”

Novel Approaches for Elongation of Fish Oils into Very-Long-Chain Polyunsaturated Fatty Acids and Their Enzymatic Interesterification into Glycerolipids

“…Reaction schemes and calculations are shown in the Figures S4 and S5 . As shown in Table 3 , the three-step elongation reported herein allowed us a significant improvement of the AE (52.71%) and PAE (6.17%) compared to the synthesis of Goruspundi et al (ref ( 32 ))/Wade et al (ref ( 49 )), indicating that more DHA used as the starting material was transformed into final product C28:6 n -3. In the case of our study, E-Factor was reduced 2.5-fold compared to the one of Goruspundi et al (ref ( 32 ))/Wade et al (ref ( 49 )), creating a lower amount of waste as well as byproducts ( Table 3 ).…”

Genotoxicity evaluation of a fish oil concentrate containing Very Long Chain Fatty Acids

“…The peak plasma level as measured in this study was between 2 and 4 hrs. In a similar study, serum samples from WT mice fed a bolus of 6 mg/kg C36 VLCFA (C36:6 n-3) showed a peak uptake of C36 at 2 h with the majority of uptake being between 2 and 8 h after bolus feeding [11] .…”

Dietary fish oil enriched in very-long-chain polyunsaturated fatty acid reduces cardiometabolic risk factors and improves retinal function

“…No other serum or retinal changes for the other measured fatty acids were observed over time, except for a small increase in retinal 28:4 levels at 24 h after dosing (p < 0.05 vs. baseline). Based on the rapid absorption of orally administered fish oil VLCPUFA concentrate, which agrees with previous observations where chemically synthesized C32:6 was used, 11 we euthanized mice following a light fasting (5 h) in the 8-week dietary study to capture the change in plasma levels of VLCPUFAs. Mice on VLCPUFA supplementation for 8 weeks showed higher levels of 24:5, 26:6, and 28:8 in the plasma, liver, brain, and eyes compared with control diet ( Figure 1 B and Table S3 ).…”

Novel Approaches for Elongation of Fish Oils into Very-Long-Chain Polyunsaturated Fatty Acids and Their Enzymatic Interesterification into Glycerolipids

“…Reaction schemes and calculations are shown in the Figures S4 and S5 . As shown in Table 3 , the three-step elongation reported herein allowed us a significant improvement of the AE (52.71%) and PAE (6.17%) compared to the synthesis of Goruspundi et al (ref ( 32 ))/Wade et al (ref ( 49 )), indicating that more DHA used as the starting material was transformed into final product C28:6 n -3. In the case of our study, E-Factor was reduced 2.5-fold compared to the one of Goruspundi et al (ref ( 32 ))/Wade et al (ref ( 49 )), creating a lower amount of waste as well as byproducts ( Table 3 ).…”

Genotoxicity evaluation of a fish oil concentrate containing Very Long Chain Fatty Acids

“…The peak plasma level as measured in this study was between 2 and 4 hrs. In a similar study, serum samples from WT mice fed a bolus of 6 mg/kg C36 VLCFA (C36:6 n-3) showed a peak uptake of C36 at 2 h with the majority of uptake being between 2 and 8 h after bolus feeding [11] .…”