Received for publication May 2, 2006.
Revised May 18, 2006.
Accepted for publication May 18, 2006.

Policosanol Inhibits Cholesterol Synthesis in Hepatoma Cells by Activation of AMP-kinase

Abstract

Policosanol is a mixture of long-chain primary alcohols that has been shown to decrease serum cholesterol in animals and in man. The hypocholesterolemic effect appears to result 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 ¹⁴C-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 pharmacologic concentrations (<5 µg/ml) policosanol and triacontanol decreased ¹⁴C-acetate incorporation into cholesterol without affecting the incorporation of ¹⁴C-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 three-fold increase in AMP-kinase phosphorylation was noted in policosanol-treated cells. As 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.

Key words: AMP kinase, HMG CoA reductase, cell culture, cholesterol synthesis, metformin, policosanol

This article has been cited by other articles:

				S. P. J. Dullens, R. P. Mensink, M. C. E. Bragt, A. K. Kies, and J. Plat Effects of emulsified policosanols with different chain lengths on cholesterol metabolism in heterozygous LDL receptor-deficient mice J. Lipid Res., April 1, 2008; 49(4): 790 - 796. [Abstract] [Full Text] [PDF]