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

Journal of Lipid Research

Jan Freark de Boer¹  Laura Mele²  Henk Wolters³  Uwe J.F. Tietge³  Gemma Brufau³  Justina C. Wolters⁴  Jan A. Kuivenhoven⁴  Vincent W. Bloks⁴  Albert K. Groen⁴  Marleen Schonewille⁵ 

[1] Department of PediatricsUniversity Medical Center Groningen, University of Groningen, Groningen, The Netherlands;To whom correspondence should be addressed;Department of Pediatrics, Section Molecular Genetics,University Medical Center Groningen, University of Groningen, Groningen, The Netherlands;Department of PediatricsUniversity Medical Center Groningen, University of Groningen, Groningen, The Netherlands;To whom correspondence should be addressed;

关键词: cholesterol/absorption;    cholesterol/biosynthesis;    liver;    intestine;    biliary cholesterol;    transintestinal cholesterol excretion;   

DOI  :  

来源: DOAJ

【 摘 要 】

Statins are competitive inhibitors of HMG-CoA reductase, the rate-limiting enzyme of cholesterol synthesis. Statins reduce plasma cholesterol levels, but whether this is actually caused by inhibition of de novo cholesterol synthesis has not been clearly established. Using three different statins, we investigated the effects on cholesterol metabolism in mice in detail. Surprisingly, direct measurement of whole body cholesterol synthesis revealed that cholesterol synthesis was robustly increased in statin-treated mice. Measurement of organ-specific cholesterol synthesis demonstrated that the liver is predominantly responsible for the increase in cholesterol synthesis. Excess synthesized cholesterol did not accumulate in the plasma, as plasma cholesterol decreased. However, statin treatment led to an increase in cholesterol removal via the feces. Interestingly, enhanced cholesterol excretion in response to rosuvastatin and lovastatin treatment was mainly mediated via biliary cholesterol secretion, whereas atorvastatin mainly stimulated cholesterol removal via the transintestinal cholesterol excretion pathway. Moreover, we show that plasma cholesterol precursor levels do not reflect cholesterol synthesis rates during statin treatment in mice. In conclusion, cholesterol synthesis is paradoxically increased upon statin treatment in mice. However, statins potently stimulate the excretion of cholesterol from the body, which sheds new light on possible mechanisms underlying the cholesterol-lowering effects of statins.

【 授权许可】

Unknown