Abstract:Vitamin A (all-trans-retinol) is metabolized to the visual chromophore (11-cis-retinal) in the eyes and to all-trans-retinoic acid, a hormone like compound, in most tissues. A key enzyme in retinoid metabolism is lecithin:retinol acyltransferase (LRAT), which catalyzes the esterification of vitamin A. The importance of LRAT is indicated by pathogenic missense and nonsense mutations, which cause devastating blinding diseases. Retinoid-based chromophore replacement therapy has been proposed as treatment for thes… Show more
“…Located in the endoplasmic reticulum, this enzyme adopts a bitopic membrane topology with a transmembrane helix at the C-terminus and an additional amphiphilic domain present at the N-terminus (Fig. 5A) [218,219]. LRAT belongs to an ancient NlpC/P60 thiol peptidase protein superfamily that includes seven representatives encoded in the human genome: two neurological sensory proteins (NSE1-2), and five H-ras-like tumor suppressors (HRASLS1-5) [220,221].…”
Section: Catalysis At the Lipid Membrane/water Interfacementioning
“…We previously observed in cells and tissues that RA concentrations increase with impaired lecithin:retinol acyltransferase (LRAT) function (23,24). LRAT acts downstream in the pathway for retinoid biosynthesis and esterifies retinol (ROL) by transferring an acyl moiety from the sn-1 position of phosphatidylcholine (25,26).…”
There is increasing recognition that dietary lipids can affect the expression of genes encoding their metabolizing enzymes, transporters, and binding proteins. This mechanism plays a pivotal role in controlling tissue homeostasis of these compounds and avoiding diseases. The regulation of retinoid biosynthesis from β-carotene (BC) is a classic example for such an interaction. The intestine-specific homeodomain transcription factor (ISX) controls the activity of the vitamin A-forming enzyme β-carotene oxygenase-1 in intestinal enterocytes in response to increasing concentration of the vitamin A metabolite retinoic acid. However, it is unclear how cells control the concentration of the signaling molecule in this negative-feedback loop. We demonstrate in mice that the sequestration of retinyl esters by the enzyme lecithin:retinol acyltransferase (LRAT) is central for this process. Using genetic and pharmacological approaches in mice, we observed that in LRAT deficiency, the transcription factor ISX became hypersensitive to dietary vitamin A and suppressed retinoid biosynthesis. The dysregulation of the pathway resulted in BC accumulation and vitamin A deficiency of extrahepatic tissues. Pharmacological inhibition of retinoid signaling and genetic depletion of the Isx gene restored retinoid biosynthesis in enterocytes. We provide evidence that the catalytic activity of LRAT coordinates the negative-feedback regulation of intestinal retinoid biosynthesis and maintains optimal retinoid levels in the body.Supplementary key words enterocytes • retinoids • carotenoids • cell signaling • metabolism • lipids • LRAT • vitamin A *For correspondence: Johannes von Lintig, johannes.vonlintig@case.edu.
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