Reduction of all-trans-retinal in the mouse liver peroxisome fraction by the short-chain dehydrogenase/reductase RRD: Induction by the PPARα ligand clofibrate

The mouse liver 16000g fraction, which contains peroxisomes, reduces all-trans-retinal, but has limited ability to dehydrogenate retinol enzymatically. Feeding mice for 2 weeks with a diet containing clofibrate (0.5%, w/w), a PPARα ligand and peroxisome proliferator, increased the 16000g fraction ∼2-fold in protein, ∼2-fold in specific activity of retinal reduction, and ∼4-fold in retinal reductase units compared to controls, and caused a 50% decrease in liver retinol. An increase in both reductase specific activity and units indicates that clofibrate/PPARα induced expression of retinal-reducing enzymes(s), in addition to increasing reductase(s) content. We expressed a cDNA from the NCBI data bank that encodes a peroxisome short-chain dehydrogenase/reductase. The enzyme, mouse retinal reductase (RRD, also known as human 2,4-dienoyl-CoA reductase), reduces all-trans-retinal [V_m = 40 nmol min^-1 (mg of protein)^-1; K_0.5 = 2.3 μM] and has 4- and 60-fold less activity with 13-cis-retinal and 9-cis-retinal, respectively. Recombinant RRD functions with both unbound and CRBP(I) (cellular retinol-binding protein)-bound retinal, but apo-CRBP(I) inhibits the reductase. RRD mRNA expression was initiated on embryo day 7. Most adult tissues assayed expressed the mRNA. Liver, kidney, and heart had the most intense expression, with much less intense expression in brain, spleen, and lung. Clofibrate feeding increased the amount of RRD protein in the 16000g fraction of liver, consistent with the clofibrate-induced increase in reductase activity. These data relate retinoid metabolism, PPARα, peroxisomes, and RRD, and are consistent with a further function of CRBP(I) in retinoid metabolism.