The role of adenosine triphosphate citrate lyase in the metabolism of acetyl coenzyme a and function of blood platelets in diabetes mellitus.
Diabetes is known to increase blood platelet activity. Activities of pyruvate dehydrogenase (PDH), adenosine triphosphate (ATP)-citrate lyase (ATPCL), acetyl-coenzyme A (acetyl-CoA) content, malonyl dialdehyde (MDA), synthesis, and platelet aggregation in resting conditions and after activation with thrombin were measured in diabetic subjects and in age- and sex-matched healthy subjects. Activities of ATPCL and PDH, acetyl-CoA content, and thrombin-evoked MDA synthesis as well as platelet aggregation in diabetes were 31%, 51%, 62%, 35%, and 21%, respectively, higher than in healthy subjects. In addition, activation of diabetic platelets caused 2 times greater release of acetyl-CoA from their mitochondria than in controls. Both 1.0 mmol/L (-)hydroxycitrate and 0.1 mmol/L SB-204490 decreased acetyl-CoA content in platelet cytoplasm along with suppression of MDA synthesis and platelet aggregation. These inhibitory effects were about 2 times greater in diabetic than in control platelets. The data presented indicate that the ATPCL pathway is operative in human platelets and may be responsible for provision of about 50% of acetyl units from their mitochondrial to cytoplasmic compartment. Increased acetyl-CoA synthesis in diabetic platelets may be the cause of their excessive activity in the course of the disease. ATPCL may be a target for its specific inhibitors as factors decreasing platelet activity.
Michno
Anna
A
Department of Laboratory Medicine, Medical University of Gdańsk, Poland.
Skibowska
Anna
A
Raszeja-Specht
Anna
A
Cwikowska
Justyna
J
Szutowicz
Andrzej
A
D001275:ATP Citrate (pro-S)-Lyase / Q000037:antagonists & inhibitors / Q000097:blood*; D000105:Acetyl Coenzyme A / Q000097:blood*; D000328:Adult; D001786:Blood Glucose / Q000032:analysis; D001792:Blood Platelets / Q000502:physiology*; D002951:Citrates / Q000494:pharmacology; D003922:Diabetes Mellitus, Type 1 / Q000097:blood*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019270:Fructosamine / Q000097:blood; D006442:Glycated Hemoglobin / Q000032:analysis; D006801:Humans; D007783:Lactones / Q000494:pharmacology; D008315:Malondialdehyde / Q000097:blood; D008875:Middle Aged; D015539:Platelet Activation / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D011768:Pyruvate Dehydrogenase Complex / Q000097:blood; D013917:Thrombin / Q000494:pharmacology
D001275:ATP Citrate (pro-S)-Lyase; D000105:Acetyl Coenzyme A; D001786:Blood Glucose; D002951:Citrates; D004791:Enzyme Inhibitors; D019270:Fructosamine; D006442:Glycated Hemoglobin; D007783:Lactones; D008315:Malondialdehyde; D011768:Pyruvate Dehydrogenase Complex; D013917:Thrombin; C112852:SB 204990; C007999:hydroxycitric acid