Studies on the mechanism for the serum cholesterollowering effect of ursodesoxycholic acid

Hepatic cholesterol biosynthesis and fecal excretion of endproducts of cholesterol metabolism

Abstract

The mechanism of the hypocholesterolemic action of ursodesoxycholic acid (α-3, β-7-dihydroxycholanic acid) that were used as choleretic is not yet understood clearly. In an atempt to throw some light on the mechanism of this hypocholesterolemic action, studies were made on the incorporation of acetate-1-¹⁴C or mevalonic acid-2-¹⁴C and the fecal excretion of choleserol endproducts originating from mevalonic acid-2-¹⁴C. Male mice were used throughout the study and were placed on a cholesterol-free diet for 2 week observation period.
1. Biosynthesis:
Ten mice remained on the cholesterol-free diet and another ten mice were fed by supplementing the cholesterol-free diet with 0.5% ursodesoxycholic acid for 10 day. At the end of experimental period, one hour before killing the mice, the animals were injected with 5μc of acetate-1-¹⁴C or 0.12μc of mevalonic acid-2-¹⁴C per 20gm of body weight. The livers were excised and the incorporation into total lipid, cholesterol, fatty acid, protein and glycogen were measured. Ursodesoxycholic acid inhibited the incorporation of acetate-1-¹⁴C into total lipid, cholesterol and fatty acids and stimulated the incoration into protein and glycogen. The incoporation of mevalonic acid-2-¹⁴C into total lipid and cholesterol were inhibited, while the incorporation into protein remained unaltered. Ursodesoxycholic acid resulted in depression of the serum and hepatic chole. sterol level and elevation of hepatic glycogen and liver weight.
The present data indicate that the locus of the effect of ursodesoxycholic acid on a rate-controlling step in cholesterol biosynthesis appears to lie some-where between me valonic acid and cholesterol and between acetate and mevalonic acid.
2. Fecal excretion:
One hour after the single injection of mevalonic acid-2-¹⁴C, animals were fed a cholesterol free diet containing 0.5% ursodesoxycholic acid for 7 days. The feces collected duaring 7 days were extracted with hot ethanol and this extracts were analysed for bile acid and sterol by the technique of Mosbach et al. The total-¹⁴C activity (ethanol extract), the total sterol-¹⁴C activity and the total bile acid-¹⁴C activity were measured. Ursodesoxycholic acid greatly increased total-¹⁴C activity excretion, the stimulation occuring in the total sterol-¹⁴C activity, while excretion of the bile acid-¹⁴C activity wa deppresed.
It is concluded that the serum cholesterol-lowering effect of ursodesoxycholic acid appers to be due mainly to the inhibition of hepatic cholesterol bisoynthesis and the increase of fecal excretion of sterols.