[Formation of mevalonic acid, sterols and bile acids from [1-14C]acetyl-CoA and [2-14C]malonyl-CoA in the liver of rabbits with experimental hypercholesterolemia].
The effect of cholesterol diet on the rate of mevalonic acid biosynthesis from 1-14C acetyl-CoA, 2-14C malonyl-CoA and the incorporation of these substrates into sterols and bile acids in rabbit liver were studied. Simultaneously, the activities of 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoA reductase) and acetyl-CoA carboxylase and the biosynthesis of fatty acids from acetyl-CoA and malonyl-CoA were measured. Hypercholesterolemia was found to be concomitant with the inhibition of acetyl-CoA carboxylase activity only in cell-free (700 g) and mitochondrial fractions and slightly decreased the incorporation of acetyl-CoA and malonyl-CoA into fatty acids in the postmitochondrial fraction. The HMG-CoA reductase activity in all subcellular fractions except for the postmicrosomal one was inhibited under these conditions. A significant decrease of acetyl-CoA incorporation and an increase in malonyl-CoA incorporation into mevalonic acid in all liver fractions except for microsomal one were observed in rabbits with hypercholesterolemia. These data provide evidence for the existence of two pathways of mevalonic acid synthesis from the above-said substrates that are differently sensitive to cholesterol. Cholesterol feeding resulted in a decreased synthesis of the total unsaponified fraction including cholesterol from acetyl-CoA, malonyl-CoA and mevalonic acid. The rate of incorporation of these substrates into lanosterol was unchanged. All the indicated substrates (acetyl-CoA, malonyl-CoA, mevalonic acid) are precursors of bile acid synthesis in rabbit liver. Cholesterol feeding and the subsequent development of hypercholesterolemia resulted in bile acid synthesis stimulation, preferentially in the formation of the cholic + deoxycholic acids from these precursors.
D000105:Acetyl Coenzyme A / Q000378:metabolism; D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D000818:Animals; D001647:Bile Acids and Salts / Q000096:biosynthesis*; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D025782:Hydroxymethylglutaryl-CoA-Reductases, NADP-dependent; D006937:Hypercholesterolemia / Q000378:metabolism*; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D008316:Malonyl Coenzyme A / Q000378:metabolism; D008798:Mevalonic Acid / Q000096:biosynthesis*; D011817:Rabbits; D013261:Sterols / Q000096:biosynthesis*; D013379:Substrate Specificity
D001647:Bile Acids and Salts; D013261:Sterols; D008316:Malonyl Coenzyme A; D000105:Acetyl Coenzyme A; D006903:Hydroxymethylglutaryl CoA Reductases; D025782:Hydroxymethylglutaryl-CoA-Reductases, NADP-dependent; D000103:Acetyl-CoA Carboxylase; D008798:Mevalonic Acid
Obrazovanie mevalonovoĭ kisloty, sterinov i zhelchnykh kislot iz [1-14C]atsetil-CoA i [2-14C]malonil-CoA v pecheni krolikov s éksperimental'noĭ giperkholesterinemieĭ.