The shunt pathway of mevalonate metabolism in the isolated perfused rat liver.
The shunt pathway of mevalonate metabolism (Edmond, J., and Popják, G. (1974) J. Biol. Chem. 249, 66-71) has been studied in isolated livers from fed rats perfused with physiological concentrations of variously labeled [14C]mevalonates. The measured rates of 14CO2 production were converted to rates of mitochondrial acetyl-CoA production from mevalonate by methods which take into account underestimations of metabolic rates derived from 14CO2 production. Our data confirm that the shunt pathway leads to mitochondrial acetyl-CoA. The apparent negligible rate of mevalonate shunting in liver, previously reported by others, stems from the very low contribution (congruent to 0.1%) of plasma mevalonate to total mevalonate metabolism in the liver. This contribution was assessed from the relative incorporations of 3H2O and [5-14C]mevalonate into sterols. In livers from fed rats, the shunt diverts about 5% of the production of mevalonate. The total rate of mevalonate shunting in the liver is about 200 times greater than in two kidneys. The liver is therefore the main site of mevalonate shunting in the rat.