PMID:23407971

Citation	Li, S, Lee, J, Zhou, Y, Gordon, WC, Hill, JM, Bazan, NG, Miner, JH and Jin, M (2013) Fatty acid transport protein 4 (FATP4) prevents light-induced degeneration of cone and rod photoreceptors by inhibiting RPE65 isomerase. J. Neurosci. 33:3178-89
Abstract	Although rhodopsin is essential for sensing light for vision, it also mediates light-induced apoptosis of photoreceptors in mouse. RPE65, which catalyzes isomerization of all-trans retinyl fatty acid esters to 11-cis-retinol (11cROL) in the visual cycle, controls the rhodopsin regeneration rate and photoreceptor susceptibility to light-induced degeneration. Mutations in RPE65 have been linked to blindness in affected children. Despite such importance, the mechanism that regulates RPE65 function remains unclear. Through unbiased expression screening of a bovine retinal pigment epithelium (RPE) cDNA library, we have identified elongation of very long-chain fatty acids-like 1 (ELOVL1) and fatty acid transport protein 4 (FATP4), which each have very long-chain fatty acid acyl-CoA synthetase (VLCFA-ACS) activity, as negative regulators of RPE65. We found that the VLCFA derivative lignoceroyl (C24:0)-CoA inhibited synthesis of 11cROL, whereas palmitoyl (C16:0)-CoA promoted synthesis of 11cROL. We further found that competition of FATP4 with RPE65 for the substrate of RPE65 was also involved in the mechanisms by which FATP4 inhibits synthesis of 11cROL. FATP4 was predominantly expressed in RPE, and the FATP4-deficient RPE showed significantly higher isomerase activity. Consistent with these results, the regeneration rate of 11-cis-retinaldehyde and the recovery rate for rod light sensitivity were faster in FATP4-deficient mice than wild-type mice. Moreover, FATP4-deficient mice displayed increased accumulation of the cytotoxic all-trans retinaldehyde and hypersusceptibility to light-induced photoreceptor degeneration. Our findings demonstrate that ELOVL1, FATP4, and their products comprise the regulatory elements of RPE65 and play important roles in protecting photoreceptors from degeneration induced by light damage.
Links	PubMed PMC3625017 Online version:10.1523/JNEUROSCI.2428-12.2013
Keywords	Acetyltransferases/pharmacology; Alcohol Oxidoreductases/metabolism; Animals; Blotting, Western; Cells, Cultured; Electroretinography; Fatty Acid Transport Proteins/genetics; Fatty Acid Transport Proteins/pharmacology; Gene Expression Regulation/physiology; Gene Library; Immunohistochemistry; Light; Mice; Mice, Inbred C57BL; Mice, Knockout; Peptide Chain Elongation, Translational; Phenotype; Real-Time Polymerase Chain Reaction; Retinal Cone Photoreceptor Cells/drug effects; Retinal Cone Photoreceptor Cells/radiation effects; Retinal Degeneration/prevention & control; Retinal Rod Photoreceptor Cells/drug effects; Retinal Rod Photoreceptor Cells/radiation effects; Retinoids/metabolism; Transfection; cis-trans-Isomerases/antagonists & inhibitors; cis-trans-Isomerases/genetics; cis-trans-Isomerases/metabolism
edit table

Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
MOUSE:S27A4		GO:0062003: negative regulation of all-trans-retinyl-ester hydrolase, 11-cis retinol forming activity	ECO:0000314:		P		“As shown in Fig. 2C, synthesis of 11cROL in the cells decreased as FATP4 expression levels increased.” UNIPROT name: S27A4 Organism: Mouse	complete CACAO 13072

References

See Help:References for how to manage references in GONUTS.