title: Manifold effects of palmitoylcarnitine on endoplasmic reticulum metabolism: 11β-hydroxysteroid dehydrogenase 1, flux through hexose-6-phosphate dehydrogenase and NADPH concentration.
abstract: With the exception of the oxidation of G6P (glucose 6-phosphate) by H6PDH (hexose-6-phosphate dehydrogenase), scant information is available about other endogenous substrates affecting the redox state or the regulation of key enzymes which govern the ratio of the pyridine nucleotide NADPH/NADP. In isolated rat liver microsomes, NADPH production was increased, as anticipated, by G6P; however, this was strikingly amplified by palmitoylcarnitine. Subsequent experiments revealed that the latter compound, well within its physiological concentration range, inhibited 11β-HSD1 (11β-hydroxysteroid dehydrogenase 1), the bidirectional enzyme which interconnects inactive 11-oxo steroids and their active 11-hydroxy derivatives. Notably, palmitoylcarnitine also stimulated the antithetical direction of 11β-HSD1 reductase, namely dehydrogenase. This stimulation of H6PDH may have likewise contributed to the NADPH accretion. All told, the result of these enzyme modifications is, in a conjoint fashion, a sharp amplification of microsomal NADPH production. Neither the purified 11β-HSD1 nor that obtained following microsomal sonification were sensitive to palmitoylcarnitine inhibition. This suggests that the long-chain amphipathic acylcarnitines, given their favourable partitioning into the membrane lipid bilayer, disrupt the proficient kinetic and physical interplay between 11β-HSD1 and H6PDH. Finally, although IDH (isocitrate dehydrogenase) and malic enzyme are present in microsomes and increase NADPH concentration akin to that of G6P, neither had an effect on 11β-HSD1 reductase, evidence that the NADPH pool in the endoplasmic reticulum shared by the H6PDH/11β-HSD1 alliance is uncoupled from that governed by IDH and malic enzyme.
authors.affiliation: Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
authors.forename: Xudong
authors.initials: X
authors.lastname: Wang
authors.forename: Gail J
authors.initials: GJ
authors.lastname: Mick
authors.forename: Edmund
authors.initials: E
authors.lastname: Maser
authors.forename: Kenneth
authors.initials: K
authors.lastname: McCormick
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000378:metabolism*; D000818:Animals; D002237:Carbohydrate Dehydrogenases / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000201:enzymology* / Q000378:metabolism; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism; D009249:NADP / Q000378:metabolism*; D010172:Palmitoylcarnitine / Q000378:metabolism*; D051381:Rats
chemical_list: D010172:Palmitoylcarnitine; D009249:NADP; D002237:Carbohydrate Dehydrogenases; C020552:galactose-6-phosphate dehydrogenase; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1