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-meth ylglutaryl coenzyme A (HMG-CoA) reductase was investigated. Cholestero l and 34 of its derivatives, including 23 potential intermediates in b ile acid biosynthesis, were incubated with cultures of human fibroblas ts for 24 h in the absence or presence of lipoproteins, and the activi ty of HMG-CoA reductase was then determined. In the absence of lipopro teins, many of the bile acid intermediates were inhibitory at a high c oncentration (2.5 mu M), while only three, 27-hydroxycholesterol, 7 al pha,27-dihydroxy-4-cholesten-3-one, and 7 alpha,12 alpha,27-trihydroxy -4-cholesten-3-one, caused a significant suppression at lower concentr ations (often >80% suppression at 0.25 mu M). Even at 0.06 mu M these sterols caused >50% suppression of the enzyme activity. In addition, 2 7-hydroxy-4-cholesten-3-one, not usually considered to be an intermedi ate in bile acid biosynthesis, was a very potent inhibitor. Comparativ e 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 3 beta-hydroxy-5 alpha-cholest-8(14)-en-15-one. The presence of lipopr oteins decreased or eliminated the inhibitory effect of most intermedi ates. Studies of the metabolism of the three most potent inhibitors in the fibroblasts indicated that the suppression was due to the compoun ds per se and not to products of their metabolism. The results show th at a few specific intermediates in the formation of bile acids are pot ent suppressors of HMG-CoA reductase. Alternative biosynthetic pathway s to bile acids may then have different regulatory roles in cholestero l biosynthesis, depending on the biological activities of the intermed iates involved.