INFLUENCE OF CHOLESTEROL SUPPLY ON CELL-GROWTH AND DIFFERENTIATION INCULTURED ENTEROCYTES (CACO-2)

When used as treatment for hypercholesterolemia HMG-CoA reductase inhi bitors will first pass through and act upon the gut mucosa. Although c holesterol availability is essential for cell growth of the intestinal mucosa adverse intestinal events are rare which is possibly due to hi therto undefined compensatory mechanisms. In the present work we there fore studied the long-term influence of mevinolin on proliferation and differentiation of CaCo-2 cells as an enterocyte model and their resp onse upon the cholesterol supply of different origin. Mevinolin caused a marked and dose-dependent inhibition of cell proliferation, microvi lli length and alkaline phosphatase. This parallel suppression was rev ersed by the addition of either exogenous free cholesterol, endogenous cholesterol from mevalonolactone or LDL but not HDL(3). Suprisingly, sucrase activity reacted in an inverse fashion to alkaline phosphatase activity. Mevinolin induced enzyme activity and this was further enha nced by mevalonolactone supply, while cholesterol and LDL normalized s ucrase to controls. In conclusion, the presence of luminal cholesterol as well as plasma LDL as the cholesterol source for the enterocyte ma y prevent mevinolin toxicity.