Adrenal insufficiency and hypoplasia have been uniformly observed in infants biochemically affected with glycerol kinase deficiency. The causal relationship between infantile glycerol kinase deficiency and adrenal insufficiency has not yet been determined. The recently elucidated role of glycerophospholipids as the mediators of trophic hormone mediated stimulation of steroidogenesis suggests that a block in the initial step of glycerophosphate synthesis, i.e., glycerol 3-phosphate production by glycerol kinase, might therefore restrict physiologic stimulation of adrenal steroid synthesis in infants with glycerol kinase deficiency. In order to test this hypothesis the de novo synthesis of glyceropphospholipids from glycerol will be investigated in isolated bovine adrenocortical cells and subcellular fractions by radioisotope tracers and TLC separation of phospholipids and compared to alternate pathways for glycerol phosphate synthesis such as glycolytic and gluconeogenic pathways. The use of glycerol kinase inhibitors (1-thioglycerol and 1-chlorohydrin) will serve as the basis for an experimental model for exploring the causal relationship between glycerol kinase deficiency and adrenal insufficiency. Adrenal glycerol kinase is partitioned intracellularly between mitochondria and soluble fractions and shows a dynamic distribution pattern dependent upon metabolite levels. The relative contribution of soluble and mitochondrial-bound glycerol kinase in the provision of glycerol phosphate for de novo phospholipid synthesis will be evaluated by radioisotope tracer methodology in cell free systems. As such, this system potentially offers itself as an excellent model for studying the role of dynamic micro-compartmentation in regulating cellular activity. In addition to improving our understanding of the causal relationship between infantile glycerol kinase deficiency and adrenal insufficiency, this research will also provide information on the regulation of de novo phospholipid synthesis and its relationship to trophic hormone mediated stimulation of steroidogenesis.
| Seltzer, W K; Angelini, C; Dhariwal, G et al. (1989) Muscle glycerol kinase in Duchenne dystrophy and glycerol kinase deficiency. Muscle Nerve 12:307-13 |
