June 2023
Volume 64, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2023
Orally Supplemented VLC-PUFA is Highly Metabolized in the Liver of Mice
Author Affiliations & Notes
  • Martin-Paul Gameli Agbaga
    Ophthalmology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States
    Cell Biology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States
  • Daniel J Stein
    Bausch & Lomb Americas Inc., Bridgewater, New Jersey, United States
  • Richard Brush
    Ophthalmology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States
  • Vicki Ea
    Ophthalmology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States
  • NEERAJ KUMAR CHAUHAN
    Ophthalmology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States
  • Lea Bennett
    Ophthalmology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States
    Physiology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States
  • Brian Rohrs
    Bausch & Lomb Americas Inc., Bridgewater, New Jersey, United States
  • Robert E Anderson
    Ophthalmology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States
  • Footnotes
    Commercial Relationships   Martin-Paul Agbaga Bausch and Lomb, America Inc, Code F (Financial Support), Retrotope Inc, Code F (Financial Support), Research to Prevent Blindness, Code F (Financial Support), P30EY021725, Code F (Financial Support), U.S. Patent (8,021,874), Code P (Patent), NIH-NEI R01 EY030513, Code R (Recipient), Bright Focus Foundation, Code R (Recipient), Knight Templar Eye Foundation, Code R (Recipient); Daniel Stein Bausch & Lomb Americas Inc., Code E (Employment); Richard Brush Bausch & Lomb Americas Inc., Code F (Financial Support), U.S. Patent (8,021,874), Code P (Patent); Vicki Ea OUHSC, Code E (Employment), Bausch & Lomb Americas Inc., Code F (Financial Support); NEERAJ CHAUHAN OUHSC, Code E (Employment); Lea Bennett OUHSC, Code E (Employment); Brian Rohrs Bausch & Lomb Americas Inc., Code E (Employment); Robert Anderson Robert Eugene Anderson Consulting LLC, Code C (Consultant/Contractor), Bausch & Lomb Americas Inc., Code F (Financial Support)
  • Footnotes
    Support  NIH Grant
Investigative Ophthalmology & Visual Science June 2023, Vol.64, 2096. doi:
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      Martin-Paul Gameli Agbaga, Daniel J Stein, Richard Brush, Vicki Ea, NEERAJ KUMAR CHAUHAN, Lea Bennett, Brian Rohrs, Robert E Anderson; Orally Supplemented VLC-PUFA is Highly Metabolized in the Liver of Mice. Invest. Ophthalmol. Vis. Sci. 2023;64(8):2096.

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      © ARVO (1962-2015); The Authors (2016-present)

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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.

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