Influence of cholesterol supply on cell growth and differentiation in cultured enterocytes (CaCo-2).
When used as treatment for hypercholesterolemia HMG-CoA reductase inhibitors will first pass through and act upon the gut mucosa. Although cholesterol availability is essential for cell growth of the intestinal mucosa adverse intestinal events are rare which is possibly due to hitherto undefined compensatory mechanisms. In the present work we therefore studied the long-term influence of mevinolin on proliferation and differentiation of CaCo-2 cells as an enterocyte model and their response upon the cholesterol supply of different origin. Mevinolin caused a marked and dose-dependent inhibition of cell proliferation, microvilli length and alkaline phosphatase. This parallel suppression was reversed by the addition of either exogenous free cholesterol, endogenous cholesterol from mevalonolactone or LDL but not HDL3. Surprisingly, sucrase activity reacted in an inverse fashion to alkaline phosphatase activity. Mevinolin induced enzyme activity and this was further enhanced by mevalonolactone supply, while cholesterol and LDL normalized sucrase to controls. In conclusion, the presence of luminal cholesterol as well as plasma LDL as the cholesterol source for the enterocyte may prevent mevinolin toxicity.
Herold
G
G
Department of Internal Medicine I, University of Ulm, FRG.
Jungwirth
R
R
Rogler
G
G
Geerling
I
I
Stange
E F
EF
D000469:Alkaline Phosphatase / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002784:Cholesterol / Q000494:pharmacology* / Q000502:physiology; D003470:Culture Media; D003864:Depression, Chemical; D006801:Humans; D007413:Intestinal Mucosa / Q000166:cytology; D008074:Lipoproteins / Q000097:blood; D008148:Lovastatin / Q000494:pharmacology*; D008798:Mevalonic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D008854:Microscopy, Electron; D008871:Microvilli / Q000648:ultrastructure; D009834:Oligo-1,6-Glucosidase / Q000378:metabolism; D013393:Sucrase / Q000378:metabolism; D013997:Time Factors; D014407:Tumor Cells, Cultured
D003470:Culture Media; D008074:Lipoproteins; C015367:mevalonolactone; D002784:Cholesterol; D008148:Lovastatin; D000469:Alkaline Phosphatase; D009834:Oligo-1,6-Glucosidase; D013393:Sucrase; D008798:Mevalonic Acid