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

Marleen Schonewille*, Jan Freark de Boer, Laura Mele, Henk Wolters, Vincent W. Bloks, Justina C. Wolters, Jan A. Kuivenhoven, Uwe J. F. Tietge, Gemma Brufau, Albert K. Groen

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

55 Citations (Scopus)

Abstract

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.(jlr) 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.-Schonewille, M., J. Freark de Boer, L. Mele, H. Wolters, V. W. Bloks, J. C. Wolters, J. A. Kuivenhoven, U. J. F. Tietge, G. Brufau, and A. K. Groen. Statins increase hepatic cholesterol synthesis and stimulate fecal cholesterol elimination in mice.

Original languageEnglish
Pages (from-to)1455-1464
Number of pages10
JournalJournal of Lipid Research
Volume57
Issue number8
DOIs
Publication statusPublished - Aug-2016

Keywords

  • cholesterol/absorption
  • cholesterol/biosynthesis
  • liver
  • intestine
  • biliary cholesterol
  • transintestinal cholesterol excretion
  • HMG-COA REDUCTASE
  • STEROL REGULATORY ELEMENT
  • LIPOPROTEIN RECEPTOR PROMOTER
  • COENZYME-A REDUCTASE
  • SYNTHESIS IN-VIVO
  • PLASMA-CHOLESTEROL
  • BILE-ACID
  • 2,3-OXIDOSQUALENELANOSTEROL CYCLASE
  • LOVASTATIN THERAPY
  • NUCLEAR-PROTEIN

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