Sex differences in the sterol and nonsterol metabolism of mevalonate.

Previous studies from this laboratory have demonstrated that the kidneys represent the major tissue site for the metabolism of circulating mevalonic acid by both the sterol and nonsterol pathways of mevalonate utilization. These earlier conclusions were based solely on observations in male rats; therefore, the present studies were carried out in both male and female rats to evaluate possible sex differences in mevalonate metabolism. Surprisingly, it was found that there are major differences in the ability of male and female rats to utilize circulating mevalonate by both of the major pathways of mevalonate metabolism. First, the female animal metabolized circulating mevalonate by the nonsterol (or “shunt”) pathway at approximately twice the rate of the male. Nephrectomy completely abolished this sex difference. Moreover, kidney slices from the female converted [5-‘4C]mevalonate to 14C02 via the shunt pathway at a rate more than twice that of the male. These findings demonstrate that the increased activity of the nonsterol mevalonate pathway in the intact female is due entirely to the greater ability of the female kidneys to metabolize mevalonate by this mechanism. The overall importance of the kidneys in mevalonate metabolism in the female was further established by the finding that approximately 70% of the mevalonate shunt activity takes place in the female kidneys as compared to 50% in the male kidneys. The second major observation in this study is that the male rat converts circulating mevalonate to cholesterol at a rate significantly greater than that of the female. It could be shown that this difference is due primarily to the greater ability of the male kidney to synthesize cholesterol. These findings represent the first demonstration of a sex difference in cholesterol synthesis either in an intact animal or by an individual animal tissue. In addition, they raise the possibility that the kidneys play a role in the well known differences in cholesterol concentration between the two sexes.