The effect of uremia on circulating mevalonate metabolism in rats

Mevalonate, an essential intermediate in cholesterol synthesis, is metabolized either to sterols or by the shunt pathway to CO 2. Previous studies have demonstrated that the kidneys are the chief site of circulating mevalonate metabolism by both pathways. Following nephrectomy, as expected, the shunt pathway was reduced by greater than 50%. However, nephrectomy resulted in an enhancement of total body sterologenesis which was due to a marked stimulation of both liver and carcass sterol synthesis. The present study unexpectedly demonstrates that, even in the presence of intact kidneys, uremia induces marked alterations in the metabolism of circulating mevalonate that are similar to those observed following nephrectomy. In rats with normal renal mass the oxidation of mevalonate to CO 2 is reduced by 57% in acutely uremic and by 34% in chronically uremic animals. This reduction in shunt pathway activity directly correlates with the degree of impairment of renal function as measured by plasma BUN and creatinine levels. In contrast to the inhibition of the shunt pathway, acute and chronic uremia is associated with a two- to threefold increase in both hepatic and carcass cholesterol and nonsaponifiable lipid synthesis from circulating mevalonate. In the liver this enhancement of sterologenesis directly correlates with plasma BUN and creatinine concentrations. Renal sterologenesis from circulating mevalonate is not significantly altered by either acute or chronic uremia. This study demonstrates that uremia per se greatly alters circulating mevalonate metabolism resulting in a marked reduction in the shunt pathway and a large stimulation of sterol synthesis in both the liver and carcass.