Possible role of mevalonate in the hypercholesterolemia seen in experimental chronic renal failure

Hypercholesterolemia may contribute to the pathogenesis of atherosclerosis associated with chronic renal failure (CRF). The mechanism underlying CRF-induced hypercholesterolemia, however, is still unknown. Mevalonate is the direct product of the rate-limiting step in cholesterol synthesis which is catalyzed by 3-hydroxy-3-methylglutaryl coenzyme A reductase. We studied the changes in mevalonate metabolism in a mouse model of CRF in which serum total cholesterol levels are directly correlated with the degree of severity of the disease as measured by serum urea levels. The results of these experiments indicated that in CRF mice, the urine mevalonate levels were significantly lower, while serum mevalonate and total cholesterol levels were significantly higher than in normal mice. We believe that by restricting the normal urinary excretion of mevalonate CRF results in more of this precursor being available for direct cholesterol synthesis. In addition, an increase in circulating mevalonate may upregulate the shunt pathway of mevalonate metabolism in the liver and peripheral tissues, thus providing increased levels of the substrates acetoacetate and acetyl coenzyme A for cholesterol synthesis.