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.

Nano-scale resolution of native retinal rod disk membranes reveals differences in lipid composition

“…Cholesterol has also been found to be necessary for rhodopsin activity, although high concentrations reduce its signaling efficiency ( Mitchell et al, 1990 , 1992 ; Palczewski, 2006 ). Indeed, many components of the membrane can have a profound impact on the function of the membrane proteins therein, making high-resolution study of membrane environments critical to the overall characterization of membrane proteins ( Zimmerman and Keys, 1989 ; Bush et al, 1991 ; Gibson and Brown, 1993 ; Suh et al, 1994 ; Albert et al, 1998 ; Agbaga et al, 2008 ; Berdeaux et al, 2010 ; Giusto et al, 2010 ; Bennett et al, 2014 ; Gorusupudi et al, 2021 ; Hamano et al, 2021 ). Early work by Falk and Fatt (1969) on the ultra-structure of ROS membranes showed a remarkable ability of the outer rim region of ROS disks to resist disruption after OsO 4 fixation.…”

ELOVL4 Mutations That Cause Spinocerebellar Ataxia-34 Differentially Alter Very Long Chain Fatty Acid Biosynthesis

“…Patients carrying the W246G and L168F mutations have no reported retinal degeneration ( 30 , 31 ). Since VLC-PUFA are predominantly enriched in the retina and are known to regulate photoreceptor health ( 9 , 41 ), we analyzed the effect of the ELOVL4 mutants on VLC-PUFA synthesis. To explore the effect of the W246G mutation on VLC-PUFA biosynthesis, we expressed Myc-tagged Elovl4 variants (WT and W246G) and GFP in HEK293 cells and confirmed protein expression.…”

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

“…Deficiency of VLC-PUFAs in the human retina is associated with STGD3 and AMD, each of which results in blindness and thus strongly affects the quality of life. More recently, Bernstein and co-workers bypassed the physiological demand for VLC-PUFA synthesis by administering 32:6 n -3 to mice by gavage . Although dietary intake of VLC-PUFAs may represent a potential therapy for macular degeneration, no suitable dietary source has been found so far nor has biotechnological production based on non-GMO or GMO organisms.…”

“…To date, current synthetic approaches are rather difficult, provide low yields, and are expensive for potential commercialization. , Therefore, we decided to develop a sustainable, cost-effective, and simple organic synthesis of VLC-PUFAs using inexpensive building blocks with a minimum of required steps. In our study, we focused on the preparation of ethyl all - cis -octacosa-10,13,16,19,22,25-hexaenoate ( 3a , C28:6 n -3) and ethyl all - cis -hexacosa-11,14,17,20,23-pentaenoate ( 3b , C26:5 n -3), precursors of the VLC-PUFA.…”