Lack of effect of lovastatin therapy on the parameters of whole-body cholesterol metabolism.

Abstract

The effects of lovastatin therapy on the parameters of body cholesterol metabolism were explored in nine hypercholesterolemic patients. Long-term cholesterol turnover studies were performed before therapy, and were repeated after 15 mo of lovastatin therapy (40 mg/d) while continuing on therapy. The major question addressed was whether a reduction in plasma cholesterol level with lovastatin would be associated with a reduction in the whole-body production rate of cholesterol or with the sizes of exchangeable body cholesterol pools as determined by the three-pool model of cholesterol turnover.

Statins increase hepatic cholesterol synthesis and stimulate fecal cholesterol elimination in mice

“…Sterol balance measurements in humans treated with pravastatin showed slight decreases in cholesterol synthesis (13)(14)(15). In contrast, Goldberg et al (16) found that cholesterol synthesis rates were unaltered in lovastatintreated patients. Kallien et al (17) measured cholesterol synthesis in human subjects treated with pravastatin or placebo in a direct way using 13 C-acetate, which is incorporated into the cholesterol molecule during cholesterol synthesis.…”

“…The effects on biliary secretion may indicate inhibition of hepatic cholesterol synthesis in humans. However, the few early studies in statin-treated humans that applied direct methods to measure cholesterol synthesis and failed to prove a reduced cholesterol synthesis (16) or even pointed toward increased cholesterol synthesis (17) indicate that whole body cholesterol synthesis may also be augmented in humans. If increased cholesterol synthesis after statin treatment is also the case in humans, then it would be important to investigate whether this would also lead to enhanced fecal excretion of neutral sterols or if the newly synthesized cholesterol undergoes a different fate.…”

The pravastatin-induced decrease of biliary cholesterol secretion is not directly related to an inhibition of cholesterol synthesis in humans

“…Nevertheless, any possible limitation of MIDA will not invalidate any of our conclusions, because these were drawn from intraindividual comparisons and the pool size was shown not to change after an HMG-CoA reductase inhibitor. 25 After pravastatin administration, the fractional synthesis in plasma (4.0%) was in the range of placebo values. Also, absolute cholesterol synthesis of the body was comparable after placebo and pravastatin treatment with an unchanged decay rate constant (turnover rate) of plasma cholesterol.…”

“…In previous studies, cholesterol synthesis after long-term inhibition of the HMG-CoA reductase in humans was variably suppressed or unchanged. 22,25,27,28,38,[45][46][47][48] This was more pronounced (Ϫ29% to Ϫ64%) if indirect indicators of body cholesterol synthesis like serum lathosterol, 24,26,45,46 urinary mevalonate, 47,48 or cholesterol synthesis in mononuclear leukocytes 22,38 were used. In comparison, only minor effects (ϩ7% to Ϫ18%) have been observed using the more quantitative estimation by the sterol balance technique.…”

“…The HMG-CoA reductase inhibitor-mediated decrease of biliary cholesterol secretion rates was considered to be a result of inhibited hepatic HMG-CoA reductase activity, 22,23 but this is unlikely to be the direct cause because it has been shown that the HMG-CoA reductase inhibitor-mediated reduction of whole body cholesterol formation is very limited. [24][25][26][27][28] The purpose of the present study was to characterize changes of biliary lipid secretion induced by the long-term administration of pravastatin, a competitive inhibitor of HMG-CoA reductase, in healthy volunteers with intact enterohepatic circulation. By use of the MIDA technique, absolute and fractional synthesis of cholesterol were determined and allowed the investigation of the relationship between de novo cholesterol synthesis and biliary lipid secretion.…”