Policosanol is a mixture of long-chain primary
alcohols that has been shown to decrease serum
cholesterol in animals and in humans. The hypocholesterolemic effect results from a decrease in
cholesterol synthesis by suppression of
HMG-CoA reductase activity, but the mechanism of this suppression and the active components of
policosanol have not been established. In the present study, we investigated the ability of
policosanol and its principal components to inhibit
cholesterol synthesis in cultured rat
hepatoma cells. Maximal inhibition by
policosanol yielded a 30% decrease in [(14)C]
acetate incorporation without evidence of cellular toxicity.
Octacosanol (C28, the major constituent of
policosanol), heptacosanol (C27), and hexacosanol (C26) yielded smaller and statistically insignificant decreases in
cholesterol synthesis, whereas
triacontanol (1-hydroxytriacontane; C30) replicated the inhibition obtained with
policosanol. At pharmacological concentrations (<5 microg/ml),
policosanol and
triacontanol decreased [(14)C]
acetate incorporation into
cholesterol without affecting the incorporation of [(14)C]
mevalonate, indicating that these compounds act at or above
HMG-CoA reductase.
Policosanol and
triacontanol did not directly inhibit
HMG-CoA reductase, and incubation of these compounds with
hepatoma cells did not affect
reductase enzyme levels. However,
reductase activity was decreased by up to 55% in lysates prepared from these cells, suggesting that
HMG-CoA reductase activity was down-regulated by
policosanol treatment. Consistent with this hypothesis, a 3-fold increase in
AMP-kinase phosphorylation was noted in
policosanol-treated cells. Because
AMP-kinase is activated by phosphorylation and is well established to suppress
HMG-CoA reductase activity, these results suggest that
policosanol or a metabolite decreases
HMG-CoA reductase activity by activating
AMP-kinase.