Structural specificity in the suppression of HMG-CoA reductase in human fibroblasts by intermediates in bile acid biosynthesis

The effect of bile acid precursors on the activity of 3-hydroxy-3- methylglutaryl coenzyme A (HMG-CoA) reductase was investigated. Cholesterol and 34 of its derivatives, including 23 potential intermediates in bile acid biosynthesis, were incubated with cultures of human fibroblasts for 24 h in the absence or presence of lipoproteins, and the activity of HMG-CoA reductase was then determined. In the absence of lipoproteins, many of the bile acid intermediates were inhibitory at a high concentration (2.5 μM), while only three, 27-hydroxycholesterol, 7α,27-dihydroxy-4-cholesten-3-one, and 7α,12α,27-trihydroxy-4-cholesten-3-one, caused a significant suppression at lower concentrations (often >80% suppression at 0.25 μM). Even at 0.06 μM these sterols caused >50% suppression of the enzyme activity. In addition, 27-hydroxy-4-cholesten-3-one, not usually considered to be an intermediate in bile acid biosynthesis, was a very potent inhibitor. Comparative studies showed that the effect of the three bile acid precursors was similar to that of 25-hydroxy-, 24-hydroxy-, and 7-oxo-cholesterol and 3β-hydroxy-5α-cholest-8(14)-en-15-one. The presence of lipoproteins decreased or eliminated the inhibitory effect of most intermediates. Studies of the metabolism of the three most potent inhibitors in the fibroblasts indicated that the suppression was due to the compounds per se and not to products of their metabolism. The results show that a few specific intermediates in the formation of bile acids are potent suppressors of HMG- CoA reductase. Alternative biosynthetic pathways to bile acids may then have different regulatory roles in cholesterol biosynthesis, depending on the biological activities of the intermediates involved.