The role of circulating mevalonate in nephrotic hypercholesterolemia in the rat.
The cause of the hypercholesterolemia that characterizes the nephrotic syndrome has never been adequately explained. The present study examines the possibility that enhanced availability of the cholesterol precursor, mevalonic acid, to the liver in the nephrotic state may result in increased hepatic cholesterogenesis. In normal animals, the kidneys are known to be the major site of the metabolism of circulating mevalonate to both cholesterol and CO2. Previous studies, using perfusion of isolated, intact kidneys, have shown that the excretion and metabolism of mevalonate are both impaired in nephrosis. The present investigation has demonstrated in vivo that puromycin aminonucleoside nephrosis results in a 25% reduction in the oxidation of mevalonate to CO2. In the same nephrotic animals, cholesterogenesis from circulating mevalonate was significantly increased in both liver and carcass. In addition, liver slices from nephrotic animals incorporated increased amounts of [5-14C]mevalonate into cholesterol when calculated per whole liver, but not per gram of liver. Oxidation of mevalonic acid by kidney slices was significantly reduced, whether expressed as per gram of tissue or per whole organ. HMG-CoA (3-hydroxy-3-methylglutaryl) reductase activity in liver of nephrotic animals was significantly increased. We conclude that, in the nephrotic state, impaired mevalonate metabolism by the kidney may contribute to enhanced cholesterogenesis by increasing delivery of mevalonate to liver and carcass; in addition, nephrosis appears to provide an undefined stimulus for HMG-CoA reductase activity in the liver, thereby providing an additional enhancement of hepatic cholesterogenesis.
D000818:Animals; D002784:Cholesterol / Q000096:biosynthesis; D005260:Female; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D006937:Hypercholesterolemia / Q000209:etiology / Q000378:metabolism*; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism; D008798:Mevalonic Acid / Q000097:blood*; D009404:Nephrotic Syndrome / Q000150:complications / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains
D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; D008798:Mevalonic Acid