Statins increase hepatic cholesterol synthesis and stimulate fecal cholesterol elimination in mice.
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.
Department of Pediatrics University Medical Center Groningen, University of Groningen, Groningen, The Netherlands m.schonewille@umcg.nl.
Marleen
M
Schonewille
Department of Pediatrics, Section Molecular Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Jan Freark
JF
de Boer
Department of Pediatrics University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Laura
L
Mele
Department of Pediatrics University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Henk
H
Wolters
Department of Pediatrics University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Vincent W
VW
Bloks
Department of Pediatrics, Section Molecular Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Justina C
JC
Wolters
Department of Pediatrics, Section Molecular Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Jan A
JA
Kuivenhoven
Department of Pediatrics University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Uwe J F
UJ
Tietge
Department of Pediatrics University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Gemma
G
Brufau
Department of Pediatrics University Medical Center Groningen, University of Groningen, Groningen, The Netherlands Department of Laboratory Medicine, Center for Liver, Digestive and Metabolic Diseases, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands Amsterdam Diabetes Center, Department of Vascular Medicine, Academic Medical Center, The Netherlands.
Albert K
AK
Groen
D000818:Animals; D002784:Cholesterol / Q000096:biosynthesis* / Q000097:blood; D004353:Drug Evaluation, Preclinical; D015870:Gene Expression / Q000187:drug effects; D005977:Glutarates / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D006937:Hypercholesterolemia / Q000097:blood / Q000188:drug therapy; D066237:Intestinal Elimination / Q000187:drug effects; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008148:Lovastatin / Q000494:pharmacology*; D008297:Male; D008810:Mice, Inbred C57BL
D005977:Glutarates; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D002784:Cholesterol; D008148:Lovastatin
biliary cholesterol; cholesterol/absorption; cholesterol/biosynthesis; intestine; liver; transintestinal cholesterol excretion