Orally Supplemented VLC-PUFA is Highly Metabolized in the Liver of Mice

Abstract

Purpose : We performed a pharmacokinetic study of a labeled very long chain polyunsaturated fatty acid (VLC-PUFA; ≥ 28 carbons) in mice to trace and assess whether oral administration could be a viable approach for treating retinal deficiency and improving ocular health. VLC-PUFA are found in the retina, which expresses the fatty acid elongase-4 (ELOVL4) enzyme that is essential for their biosynthesis. Mutations in ELOVL4 cause macular degeneration in Autosomal Dominant Stargardt-like 3 (STGD3) patients, and VLC-PUFA are decreased in retina of Age-Related Macular Degeneration (AMD) patients, which suggests that dietary supplementation of VLC-PUFA could rescue retinal function. However, there is no known dietary source of these fatty acids. To assess whether oral supplementation could increase retinal VLC-PUFA levels and improve retinal function, we fed a labeled VLC-PUFA to mice for 11 weeks.

Methods : Eight-week-old C57BI/6J mice were started on an AIN-93G diet containing 0.1% (w/w) labeled VLC-PUFA . Liver, plasma, and retina were collected at 9, 11, 13, 16, and 19 weeks of age and fatty acid analyses performed. Feces were collected to determine intestinal absorption. Electroretinograms (ERG) were performed at 8 weeks (prior to starting the diet) and 19 weeks (prior to tissue collection) of age.

Results : The VLC-PUFA was highly absorbed in the intestine (greater than 90%). At all timepoints, there was no detectable labeled VLC-PUFA in the retina. Surprisingly, after just 1 week of supplementation, there was a significant amount of labeled EPA, DPA, and DHA in the liver, plasma and retina, indicating that almost all of the VLC-PUFA had been retro-converted to these shorter chain PUFAs. Labeled VLC-PUFAs were observed in the retina after 5 weeks of dosing and attributed to elongated shorter chain species. This rapid catabolism persisted throughout the entire 11 week feeding period. ERG analysis revealed no observable improvement in retinal function after 11 weeks on the labeled VLC-PUFA diet.

Conclusions : Although highly absorbed in the intestine, the tested VLC-PUFA experienced significant first-pass metabolism in the liver when delivered orally by direct feeding to mice. As a result, there is no accumulation of dietary VLC-PUFA in the retina after 11 weeks of supplementation and no observable improvement in ERG in the mouse model.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.