The quantitative role of the kidneys in the in vivo metabolism of mevalonate.

Abstract

The roles of the sterol and nonsterol pathways in the metabolism of circulating mevalonate have been estimated in the intact rat. On an average, the sterol pathway accounts for 74 per cent of the mevalonate metabolized, while the nonsterol, or shunt, pathway is responsible for 26 per cent of the mevalonate metabolized in the whole animal. The contribution of the kidneys to each of these processes was evaluated by two approaches. First, the localization of labeled sterols and sterol precursors derived from [14C]mevalonate was determined in each of the major tissues of the body and, second, the effect of nephrectomy upon mevalonate metabolism by the sterol and shunt mechanisms was examined. The results confirm our earlier conclusion that the kidneys represent the primary tissue site of conversion of circulating mevalonate to sterols and sterol precursors. In the present study, it was shown that by 6 h after administration of [14C]mevalonate, the major end product of mevalonate metabolism in the kidneys is cholesterol and that, moreover, the kidneys are responsible for most of the cholestreol synthesized in the intact animal from injected mevalonate. Following nephrectomy, the extrarenal tissues can readily assume the dominant role normally played by the kidneys in synthesizing cholesterol and other sterols from circulating mevalonate. The major observation of the present study is that the kidneys represent the primary site of mevalonate metabolism by the shunt pathway, in that nephrectomy results in approximately a 60 per cent decrease in the mevalonate metabolized by the shunt pathway. These studies, therefore, reinforce and expand the evidence that the kidneys represent the most important single tissue site for the metabolism of circulating mevalonate.