Sustained and selective suppression of intestinal cholesterol synthesis by Ro 48-8071, an inhibitor of 2,3-oxidosqualene:lanosterol cyclase, in the BALB/c mouse.
The small intestine plays a fundamentally important role in regulating whole body cholesterol balance and plasma lipoprotein composition. This is articulated through the interplay of a constellation of genes that ultimately determines the net amount of chylomicron cholesterol delivered to the liver. Major advances in our insights into regulation of the cholesterol absorption pathway have been made using genetically manipulated mouse models and agents such as ezetimibe. One unresolved question is how a sustained pharmacological inhibition of intestinal cholesterol synthesis in vivo may affect cholesterol handling by the absorptive cells. Here we show that the lanosterol cyclase inhibitor, Ro 48-8071, when fed to BALB/c mice in a chow diet (20 mg/day/kg body weight), leads to a rapid and sustained inhibition (>50%) of cholesterol synthesis in the whole small intestine. Sterol synthesis was also reduced in the large intestine and stomach. In contrast, hepatic cholesterol synthesis, while markedly suppressed initially, rebounded to higher than baseline rates within 7 days. Whole body cholesterol synthesis, fractional cholesterol absorption, and fecal neutral and acidic sterol excretion were not consistently changed with Ro 48-8071 treatment. There were no discernible effects of this agent on intestinal histology as determined by H&E staining and the level of Ki67, an index of proliferation. The mRNA expression for multiple genes involved in intestinal cholesterol regulation including NPC1L1 was mostly unchanged although there was a marked rise in the mRNA level for the PXR target genes CYP3A11 and CES2A.
Departments of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX, United States. Electronic address: jen-chieh.chuang@utsouthwestern.edu.
Jen-Chieh
JC
Chuang
Pathology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX, United States. Electronic address: mvalasek@ucsd.edu.
Mark A
MA
Valasek
Departments of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX, United States. Electronic address: adam.lopez@utsouthwestern.edu.
Adam M
AM
Lopez
Departments of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX, United States. Electronic address: kenneth.posey@utsouthwestern.edu.
Kenneth S
KS
Posey
Departments of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX, United States; Physiology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX, United States. Electronic address: joyce.repa@utsouthwestern.edu.
Joyce J
JJ
Repa
Departments of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX, United States. Electronic address: stephen.turley@utsouthwestern.edu.
Stephen D
SD
Turley
D000818:Animals; D001384:Azetidines / Q000494:pharmacology; D001577:Benzophenones / Q000494:pharmacology*; D002784:Cholesterol / Q000008:administration & dosage / Q000096:biosynthesis*; D004032:Diet; D000069438:Ezetimibe; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007421:Intestine, Small / Q000187:drug effects* / Q000378:metabolism; D019751:Intramolecular Transferases / Q000037:antagonists & inhibitors*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008647:Mesocricetus; D051379:Mice; D008807:Mice, Inbred BALB C; D011973:Receptors, LDL / Q000235:genetics; D019821:Simvastatin / Q000494:pharmacology; D013045:Species Specificity
D001384:Azetidines; D001577:Benzophenones; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011973:Receptors, LDL; C105726:Ro 48-8071; D002784:Cholesterol; D019821:Simvastatin; D019751:Intramolecular Transferases; C021924:lanosterol synthase; D000069438:Ezetimibe
Cholesterol absorption; Enterocyte; Ezetimibe; Liver; Statins