title: Reduction in cholesterol synthesis in response to serum starvation in lymphoblasts of a patient with Barth syndrome.
abstract: Barth syndrome is a rare X-linked disease in which mild hypocholesterolemia is observed in some patients. We investigated cholesterol biosynthesis in lymphoblasts from a normal and age-matched Barth syndrome patient. Control and Barth syndrome (DeltaTAZ1) lymphoblasts were incubated in the presence or absence of serum to induce cholesterol synthesis and hydroxymethylglutaryl-coenzyme A reductase activity and expression, and cholesterol biosynthesis from radioactive precursors was determined. Cholesterol biosynthesis from [2-14C]pyruvate was stimulated 2-fold in control cells, but was unchanged in DeltaTAZ1 lymphoblasts, and from [1-14C]acetate was stimulated 77% in control but only 26% in DeltaTAZ1 lymphoblasts upon serum removal, indicating a lower ability of DeltaTAZ1 cells to upregulate cholesterol biosynthesis. The reason was an inability to increase hydroxymethylglutaryl-coenzyme A reductase activity, which was already near maximum in DeltaTAZ1 lymphoblasts, in response to serum removal, compared with control cells. The reduced ability to increase hydroxymethylglutaryl-coenzyme A reductase enzyme activity in DeltaTAZ1 lymphoblasts was due to a decrease in hydroxymethylglutaryl-coenzyme A reductase messenger RNA. Although total cholesterol levels are similar under standard culture conditions, DeltaTAZ1 lymphoblasts have a diminished capacity to respond to increased demand for cholesterol biosynthesis because of an already elevated level of synthesis under standard culture conditions.
authors.affiliation: Department of Pharmacology and Therapeutics, Center for Research and Treatment of Atherosclerosis, Center on Aging, Faculty of Medicine, University of Manitoba, Winnipeg, MB, Canada.
authors.forename: Kristin D
authors.initials: KD
authors.lastname: Hauff
authors.forename: Grant M
authors.initials: GM
authors.lastname: Hatch
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D019342:Acetic Acid / Q000493:pharmacokinetics; D000217:Acyltransferases; D056889:Barth Syndrome / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002250:Carbon Radioisotopes / Q000493:pharmacokinetics; D002478:Cells, Cultured; D002784:Cholesterol / Q000096:biosynthesis*; D016895:Culture Media, Serum-Free / Q000494:pharmacology*; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics / Q000378:metabolism; D008214:Lymphocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D019289:Pyruvic Acid / Q000493:pharmacokinetics; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism; D013217:Starvation / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics
chemical_list: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D002250:Carbon Radioisotopes; D016895:Culture Media, Serum-Free; D011973:Receptors, LDL; D014157:Transcription Factors; D019289:Pyruvic Acid; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; D000217:Acyltransferases; C108675:TAFAZZIN protein, human; D019342:Acetic Acid