Publication

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

Schonewille, M., de Boer, J. F., Mele, L., Wolters, H., Bloks, V. W., Wolters, J. C., Kuivenhoven, J. A., Tietge, U. J. F., Brufau, G. & Groen, A. K., Aug-2016, In : Journal of Lipid Research. 57, 8, p. 1455-1464 10 p.

Research output: Contribution to journalArticleAcademicpeer-review

Copy link to clipboard

Documents

  • Statins increase hepatic cholesterol synthesis and stimulate fecal cholesterol elimination

    Final publisher's version, 1.03 MB, PDF document

    Request copy

DOI

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
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

ID: 39474531