Policosanol modulates HMG-CoA reductase activity in cultured fibroblasts.
ABSTRACT Cholesterol biosynthesis is strictly controlled by 3-hydroxy-3-methylglutaryl Coenzyme A (HMG-CoA) reductase.
Transfer of cultured fibroblasts to a lipid-depleted medium (LDM) up-regulates the enzyme levels. This, in turn, is followed by an accelerated biosynthesis of cholesterol.
Exposure of Vero fibroblasts to LDM and policosanol (0.5-50 microg/mL), a new cholesterol-lowering drug purified from sugarcane (Saccharum officinarum L.) wax, decreased in a dose-dependent manner cholesterol biosynthesis from [14C]-acetate and 3H-water, but not from [14C]-mevalonate.
This suggests an effect on HMG-CoA reductase, the rate-controlling enzyme in cholesterol biosynthesis. When enzyme activity was measured in the presence of various concentrations of policosanol (0.5-50 microg/mL), reductase was not suppressed. Therefore, there was no evidence for a competitive or noncompetitive inhibition of enzyme activity. However, after treatment of intact cells with policosanol (50 microg/mL) in the presence of LDM, a suppressive effect on enzyme activity was observed, suggesting a modulatory effect of policosanol on reductase activity. The previous inhibition of enzyme up-regulation by policosanol suggests to date a depression of de novo synthesis of HMG-CoA reductase and/or stimulation of its degradation. However, the exact mechanism by which policosanol inhibits the activity of HMG-CoA reductase still remains unclear. Further studies are needed to clarify the precise mechanism of its inhibitory action on cholesterol biosynthesis.
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ABSTRACT: Hypercholesterolemia is a well-established modifiable cardiovascular risk factor and its treatment is an essential aim in preventing cardiovascular disease. Current guidelines highlight lifestyle intervention as a primary issue in the treatment of the patient with hypercholesterolemia. Therapeutic lifestyle changes are often insufficient to achieve desirable cholesterol levels. This is particularly true for high risk patients; however, also low risk patients, whose cholesterol levels are not necessarily far from recommended targets, have either sub-optimal or even significantly increased lipid levels. Nutraceuticals are borderline devices between nutrients and drugs providing a supplementation of particular nutrients with beneficial effects on health. Several nutraceuticals have been suggested to improve plasma lipid profile. The literature counted over 40 nutraceutical substances with a supposed beneficial effect on lipid metabolism; for some of them a number of clinical trials highlighted a cholesterol lowering effect and a possible positive influence on cardiovascular prognosis. The aim of this article is to review the main evidences supporting or denying the efficacy and safety of some of the most commonly used nutraceuticals with supposed cholesterol lowering activity.European Journal of Internal Medicine 07/2014; 25(7). DOI:10.1016/j.ejim.2014.06.008 · 2.30 Impact Factor
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ABSTRACT: Policosanol is a mixture of long-chain primary aliphatic alcoholspurified from sugar cane wax that has cholesterol lowering and antiplatelet effects. Omega-3 fatty acids (FA) have triglyceride lowering and antiplatelet effects. Combination treatment with policosanol and omega-3 FA (Ω23FA) has been associated with significant inhibition of platelet aggregation in rabbits compared with either drug alone. The aim of this study was to investigate the effects of combination treatment with Ω3FA (1 g/d) and policosanol (Ω3FA+Poli) compared with Ω3FA (1 g/d) plus placebo (Ω3FA+Pla) on platelet aggregation in human patients with hypercholesterolemia. This randomized, double-blind, clinical study at the Surgical Medical Research Center (Havana City, Cuba) recruited outpatients from lipid clinics, with some atherosclerotic risk factors. Outpatients of both sexes aged 20 to 75 years with serum total cholesterol (TC) levels ≥5 and <6 mmol/L were eligible to enroll. They were included in the study at the end of a 4-week diet stabilization period if their platelet aggregation to arachidonic acid (AA) was ≥50% and serum TC level remained ≥5 mmol/L. Patients were then evenly randomized to receive Ω3FA (1 g/d) + placebo or Ω3FA (1 g/d) + policosanol (10 mg/d) to be taken PO with the evening meal for 21 days. Treatment was assigned according to a randomization code using balanced blocks and a 1:1 allocation ratio. Inhibition of platelet aggregation to AA was the primary efficacy variable, while effects on platelet aggregation to collagen and epinephrine and on lipid profile were secondary variables. Drug compliance and adverse events (AEs) were monitored. Tolerability was assessed using physical examinations and laboratory test results. Sixty-four subjects were initially enrolled. Fifty-four patients (30 women, 24 men; mean [SD] age, 58.4  years, [range, 40-70 years]) met the inclusion criteria and were randomized to treatment; 2 groups of 27. After 21 days, platelet aggregation to AA was significantly inhibited in the 2 groups. Ω3FA+Poli inhibited platelet aggregation to all agonists by ≥20%. Platelet aggregation to AA 1.0 and 1.5 mM was inhibited with combination treatment (39.6% and 33.9%, respectively; both P < 0.001 vs baseline; P < 0.001 and P < 0.01, respectively, vs Ω3FA+Pla) and with Ω3FA+Pla (11.0% and 13.3%; both, P < 0.001). Combination treatment was more effective in inhibiting platelet aggregation to AA 1.0 and 1.5 mM in 28.6% (P < 0.001) and 20.6% (P < 0.01), respectively. Platelet aggregation to collagen 1 μg/mL was significantly inhibited with combination treatment and with Ω3FA+Pla compared with baseline (43.2% and 15.1%, respectively; both, P < 0.001), but the effects of combination treatment were significantly greater (P < 0.01). Platelet aggregation to epinephrine 0.1 mM was inhibited with Ω3FA+Poli and Ω3FA+Pla (34.8% and 20.1%; both, P < 0.001), with similar results for both groups. Bleeding time did not change significantly for either group and Ω3FA+Pla did not significantly change the lipid profile. Combination treatment did significantly reduce levels of low-density lipoprotein cholesterol (LDL-C) (17.4%; P < 0.001 vs baseline, P < 0.05 vs Ω3FA+Pla) and TC (10.1%; P < 0.001 vs baseline, P < 0.05 vs Ω3FA+Pla), increase high-density lipoprotein cholesterol (HDL-C) levels (18.0%; P < 0.001 vs baseline), but did not significantly change triglyceride levels. Three patients (2 from the Ω3FA+Poli group and 1 from the Ω3FA+Pla group) withdrew from the trial, though none were due to AEs. Two patients receiving combination treatment reported mild AEs (headache). All treatments were well tolerated. In these patients, policosanol (10 mg/d) administered concomitantly with Ω3FA (1 g/d) enhanced the inhibition of platelet aggregation to AA and collagen, but not to epinephrine, compared with Ω3FA+Pla, without significantly affecting bleeding time. Concomitant treatment was also associated with reduced levels of LDL-C and TC and raised HDL-C levels. All treatments were well tolerated.Current Therapeutic Research 05/2006; 67(3):174-92. DOI:10.1016/j.curtheres.2006.06.004 · 0.45 Impact Factor
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ABSTRACT: In this study, we investigated whether tetracosanol, an aliphatic alcohol isolated from Saccharum sinense, enhances insulin receptor kinase activity to exhibit an insulin synergistic effect in vitro and in vivo. The insulin plus tetracosanol enhanced insulin receptor kinase showed that AKT activity was down-regulated by S961 in differentiated L6 myotubes. Meanwhile, insulin plus tetracosanol restored the ability of glucose transporter translocation and glucose uptake in differentiated myotubes with S961-induced insulin resistance in vitro. The modification of carbon chain lengths and the hydroxyl group of tetracosanol showed that it served as a critical chemical structure for the glucostasis effect in vivo. This study provides new evidence to show that tetracosanol can improve glycaemic control via insulin receptor kinase activity induced and leads to the enhancement of glucose transporter translocation to improve glucose uptake. The hydroxyl group of tetracosanol plays a critical role for insulin receptor kinase activity.Journal of Functional Foods 04/2015; 14. DOI:10.1016/j.jff.2015.01.033 · 4.48 Impact Factor