Transphosphatidylation of sugar alcohols and its implications for the pathogenesis of diabetic complications.
Glucose-induced sorbitol accumulation and attendant alterations in cellular myo-inositol and phosphoinositide metabolism have been invoked in the pathogenesis of diabetic complications; however, direct effects of sorbitol on membrane phospholipid composition or metabolism have never been evaluated. Phospholipase D catalyses the transphosphatidylation of ethanol into phosphatidylcholine to yield phosphatidylethanol, an "abnormal" phospholipid whose content in rat brain is increased by chronic ethanol ingestion. Analogous transphosphatidylation of sorbitol or other polyols whose concentration is elevated in diabetes was explored in vitro and in glucose-exposed cultured human retinal pigment epithelial cells. Phosphatidylcholine and varying concentrations of sorbitol, galactitol, mannitol and glucose were incubated with peanut phospholipase D in sodium acetate buffer for varying time periods. Thin layer chromatography revealed new phospholipid bands whose hydrolysis by phospholipase D liberated a water-soluble compound that cochromatographed with sorbitol on gas-liquid chromatography, and whose concentration increased in a time- and concentration-dependent fashion. Identical transphosphatidylation activity was demonstrated in a rat brain synaptosomal fraction. Phospholipase D hydrolysis of lipids from human retinal pigment epithelial cells constitutively overexpressing the aldose reductase gene yielded a sorbitol-like compound whose appearance was increased by glucose exposure and was decreased by an aldose reductase inhibitor. Thus, glucose-induced aldose reductase inhibitor sensitive sorbitol accumulation might induce the formation of "phosphatidylsorbitol" through a transphosphatidyl mechanism that may contribute to altered membrane phospholipid metabolism in diabetes.
Nakamura
J
J
Department of Internal Medicine, University of Michigan, Ann Arbor 48109-0354.
Lattimer
S A
SA
Greene
D A
DA
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors; D000818:Animals; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D002849:Chromatography, Gas; D002855:Chromatography, Thin Layer; D003921:Diabetes Mellitus, Experimental / Q000209:etiology* / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D048289:Imidazolidines; D010712:Phosphatidic Acids / Q000378:metabolism*; D010739:Phospholipase D / Q000378:metabolism; D010743:Phospholipids / Q000096:biosynthesis*; D010857:Pigment Epithelium of Eye / Q000378:metabolism; D051381:Rats; D013012:Sorbitol / Q000378:metabolism*; D013574:Synaptosomes / Q000378:metabolism
D007093:Imidazoles; D048289:Imidazolidines; D010712:Phosphatidic Acids; D010743:Phospholipids; D013012:Sorbitol; D000449:Aldehyde Reductase; D010739:Phospholipase D; C026411:sorbinil