Genetic Evidence That Retinaldehyde Dehydrogenase Raldh1 (Aldh1a1) Functions Downstream of Alcohol Dehydrogenase Adh1 in Metabolism of Retinol to Retinoic Acid

Abstract

Vitamin A (retinol) is a nutrient that is essential for developmental regulation but toxic in large amounts. Previous genetic studies have revealed that alcohol dehydrogenase Adh1 is required for efficient clearance of excess retinol to prevent toxicity, thus demonstrating that the mechanism involves oxidation of excess retinol to retinoic acid (RA). Whereas Adh1 plays a dominant role in the first step of the clearance pathway (oxidation of retinol to retinaldehyde), it is unknown what controls the second step (oxidation of retinaldehyde to RA). We now present genetic evidence that aldehyde dehydrogenase Aldh1a1, also known as retinaldehyde dehydrogenase Raldh1, plays a dominant role in the second step of retinol clearance in adult mice. Serum RA levels following a 50 mg/kg dose of retinol were reduced 72% in Raldh1 ؊⁄؊ mice and 82% in Adh1 ؊⁄؊ mice. This represented reductions in RA synthesis of 77-78% for each mutant after corrections for altered RA degradation in each. After retinol dosing, serum retinaldehyde was increased 2.5-fold in Raldh1 ؊⁄؊ mice (indicating defective retinaldehyde clearance) and decreased 3-fold in Adh1 ؊⁄؊ mice (indicating defective retinaldehyde synthesis). Serum retinol clearance following retinol administration was decreased 7% in Raldh1 ؊⁄؊ mice and 69% in Adh1 ؊⁄؊ mice. LD 50 studies indicated a small increase in retinol toxicity in Raldh1 ؊⁄؊ mice and a large increase in Adh1 ؊⁄؊ mice. These observations demonstrate that Raldh1 functions downstream of Adh1 in the oxidative metabolism of excess retinol and that toxicity correlates primarily with accumulating retinol rather than retinaldehyde.

Vitamin A supplementation in early life affects later response to an obesogenic diet in rats

“…45 Known RA-mediated transcriptional responses were enhanced in the tissues of RE rats at weaning (day 21), including downregulation of Aldh 1a1 expression in iWAT. 13,49 Downregulation of Aldh 1a1 in the face of upregulation of the RA-degrading enzyme CYP26a1 is suggestive of a homeostatic mechanism to keep constant intracellular RA levels in WAT.…”

“…44 ISX mRNA levels in intestine and CYP26a1 mRNA levels in liver and iWAT were higher in the RE rats than in the control rats (Figures 2a-c), indicating increased RA-mediated transcriptional responses in tissues of RE-treated animals. Aldehyde dehydrogenase 1a1 (Aldh 1a1), which catalyzes RA production from retinaldehyde, 45 was expressed in tissues of 21-day-old rats, and its mRNA levels in iWAT, but not in the liver, were downregulated in the RE rats (Figures 2d and e).…”

Metabolism and Transactivation Activity of 13,14-Dihydroretinoic Acid

“…Adh1Ϫ/Ϫ and Raldh1Ϫ/Ϫ mice were much more sensitive to ROL-induced toxicity than their wild type counterparts (49,50). It was proposed that conversion of ROL to RA protects against excess levels of dietary ROL.…”

Enzymology of retinoic acid biosynthesis and degradation

“…ALDH1A1 is not essential for embryogenesis, but it may have a role in atRA biosynthesis during adulthood. The in vivo role of ALDH1A1 in atRA biosynthesis is evidenced by the fact that, whereas Aldh1a1 Ϫ / Ϫ mice are viable and have normal morphology of the retina, the livers of Aldh1a1 Ϫ / Ϫ mice display reduced atRA biosynthesis and increased serum retinaldehyde levels after treatment with retinol ( 107,108 ). The primary goal of this review was to emphasize the differences in catalytic properties of the three major retinaldehyde dehydrogenases.…”