Sex difference in human mevalonate metabolism

Area of Science:

• Biochemistry
• Human Physiology
• Metabolic Pathways

Background:

• Mevalonate metabolism involves a major sterol pathway for cholesterol synthesis and a shunt pathway leading to CO2 oxidation.
• Previous studies in rats indicated sex-based differences in mevalonate metabolism, with females favoring the shunt pathway and males favoring cholesterol synthesis.

Purpose of the Study:

• To investigate whether sex differences in mevalonate metabolism observed in rats are also present in humans.
• To compare the metabolic fate of circulating mevalonate between men and women.

Main Methods:

• Six men and five premenopausal women received injections of R,S-[5-14C]mevalonate.
• Expired 14CO2 was continuously monitored using an ionization chamber to quantify mevalonate shunt pathway activity.
• Plasma and erythrocyte [14C]cholesterol levels were measured to assess cholesterol synthesis.

Main Results:

• Female subjects expired significantly more (16.5%) of the injected mevalonate as 14CO2 compared to male subjects (9.8%) (P < 0.001).
• No significant sex differences were found in plasma and erythrocyte [14C]cholesterol levels.
• These findings demonstrate a distinct sex difference in human mevalonate metabolism.

Conclusions:

• Human beings exhibit a sex difference in mevalonate metabolism, with women showing greater activity in the mevalonate shunt pathway.
• The clinical significance of this increased shunt activity on overall cholesterol balance in women remains to be determined.