INCREASED 27-HYDROXYLATION OF CHOLESTEROL IN PRIMARY HYPERCHOLESTEROLEMIA

BACKGROUND. The first step in the alternate biosynthetic pathway of bile acid synthesis from cholesterol is represented by hydroxylation on cholesterol side chain, and is catalyzed by the mitochondrial enzyme 27-hydroxylase, which is present both in liver and in extrahepatic tissues. The physiological relevance of such pathway is still unknown, even if it is believed to play a role in the degradation of cholesterol outside the liver, possibly in the vessel wall (1).AIM of the present study was to investigate the rates of cholesterol 27-hydroxylation “in vivo” in patients with primary hypercholesterolemia, and to assess the effects induced by treatment with statin drugs.METHODS. Seven patients with primary hypercholesterolemia (FH or polygenic hypercholesterolemia) underwent determination of cholesterol 27-hydroxylation rates “in vivo” by means of continuous i.v. infusion of deuterated 27-hydroxycholesterol over 2 hr. Plasma deuterated 27-hydroxycholesterol was assayed after standard sterol extraction by gas chromatography-mass spectrometry (GC-MS) with 19-hydroxycholesterol as an internal standard. The rate of production of 27-hydroxycholesterol was calculated as the ratio between isotope enrichment and infusion rate (1,2). The data were compared with those obtained in a population of 4 normocholesterolemic controls. In some patients the infusions were repeated during treatment with standard doses of atorvastatin (5 infusions) or rosuvastatin (5 infusions).RESULTS. The rates of 27-hydroxylation were significantly higher in untreated hypercholesterolemic patients, compared with controls (8.7±2.7 mg/h vs 3.7±1.2 mg/h, mean ± SD, p < 0.01). After treatment with statins, hydroxylation rates dropped by nearly 50% along with a drastic reduction in plasma total and LDL-cholesterol, so that the ratio between 27-hydroxylation rates and plasma cholesterol was unchanged. No difference was detectable between the two statins. Linear regression analysis showed a correlation trend between plasma cholesterol and 27-hydroxylation rates.CONCLUSIONS. Primary hypercholesterolemia associates with increased rates of cholesterol 27-hydroxylation, which tend to normalize during hypocholesterolemic treatment with statins. The correlation between plasma cholesterol levels and 27-hydroxylation support the view that the latter may act as a compensatory mechanism in a condition of larger plasma cholesterol pool. A regulatory role for hepatic and extrahepatic nuclear receptors seems reasonable. These data might encourage novel pharmacological approaches for the management of hypercholesterolemia and the prevention of atherosclerosis.