While Rhodopsin is essential for sensing light for vision it also mediates light-induced apoptosis of photoreceptors in mouse. 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 11retinaldehyde 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 NVP-231 cytotoxic all-retinaldehyde and hyper susceptibility 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. Introduction The visual cycle provides 11-retinaldehyde (11cRAL) chromophore to photoreceptors to regenerate visual pigments that sense light. Although the visual cycle is essential for sustaining vision its all-trans retinaldehyde (aretinyl esters (aretinyl palmitate (aretinol (11are associated with blinding diseases (Gu et al. 1997 Marlhens et al. 1997 Disease-causing mutations severely reduce isomerase activity (Chen et al. 2006 Takahashi et al. 2006 Philp et al. 2009 Mice with a null mutation in cannot synthesize 11mice show slowing of 11(Moulson et al. 2007 mice were maintained in 12 h cyclic light at 30 lux. mice (shown as hereafter) are transgenic/mutant mice expressing transgenic FATP4 in keratinocytes (via the promoter) of a FATP4-deficient mouse line called wrinkle free which has a spontaneous retrotransposon insertion in a coding exon of (Moulson et al. 2003 The skin defect-based neonatal lethality of mice is rescued by keratinocyte-specific GRK4 expression of FATP4 (Moulson et al. 2007 Because the original mice were heterozygous for the Leu450Met variation in mice homozygous for the Leu450 or Met450 allele. The Leu450 and Met450 alleles were verified by DNA sequencing using mutation was confirmed by PCR as described previously (Moulson et al. 2007 129 and C57BL/6J mice were used as wild-type (WT) controls against age-matched mice with Leu450 or Met450 alleles respectively. Two to three month old NVP-231 mice of either sex were used for NVP-231 the experiments unless otherwise specified. All mouse experiments were approved by the Institutional Pet Care and Make use of Committee for LSUHSC and performed relating to guidelines founded from the Association for Study in Eyesight and Ophthalmology Declaration for the usage of Pets in Ophthalmic and Eyesight Study. Cell tradition and transfection The 293T-LRC cells (Jin et al. 2005 stably expressing LRAT (L) RPE65 (R) as well as the mobile retinaldehyde-binding proteins (C) were taken care of in DMEM (Invitrogen) supplemented with 10% heat-inactivated fetal bovine serum (FBS) NVP-231 and antibiotics (100 products/ml penicillin G and 100 μg/ml streptomycin) at 37°C under 5% CO2. Transient transfection of plasmid DNA in to the cells was performed using the PolyJet transfection reagent (SignaGen Laboratories). Testing from the RPE expression collection Library testing was completed as referred to previously (Jin et al. 2005 The collection pool.