Delineation of molecular changes in intrahepatic cholesterol metabolism resulting from diminished cholesterol absorption

Abstract

The absorption of cholesterol by the small intestine is a major route for the net entry of cholesterol into the body and can therefore affect the plasma low density lipoprotein-cholesterol (LDL-C) concentration. These studies used ezetimibe, a potent inhibitor of cholesterol absorption, to delineate the biochemical and molecular changes in intrahepatic metabolism and biliary lipid secretion when there is a major reduction in chylomicron cholesterol delivery to the liver. In female LDL receptor (LDLR)-deficient (LDLR ؊ / ؊ ) mice fed a basal diet containing ezetimibe (0-10 mg/day/ kg body weight), cholesterol absorption was reduced up to 91%, fecal neutral sterol excretion was increased up to 4.7-fold, and plasma total cholesterol concentrations decreased by up to 18%. Blocking cholesterol absorption prevented the accumulation of very low density lipoproteins and LDL in the circulation of LDLR ؊ / ؊ mice fed a lipid-rich diet. In female LDLR ؉ / ؉ mice fed the lipid-rich diet with ezetimibe, the relative mRNA level for the LDLR in the liver was 2-fold greater than in matching mice given the lipid-rich diet alone. We conclude that in the mouse the reduction in plasma LDL-C levels induced by blocking cholesterol absorption reflects both a diminished rate of LDL-C production and a modest increase in hepatic LDLR expression.

Ezetimibe: cholesterol lowering and beyond

“…In this model, ezetimibe reduces the production of VLDL and LDL [34]. Ezetimibe also induces an increase in the expression of LDL receptors in LDL r +/+ mice.…”

“…Reductions in plasma and hepatic TG are observed in mice and hamsters administered ezetimibe [34]. Given that ezetimibe does not block fat absorption, decreased TG levels are likely attributed to a secondary effect resulting from the reduced delivery of cholesterol from the intestine to the liver, which in turn decreases VLDL production.…”

“…Ezetimibe inhibits intestinal cholesterol absorption and results in increased intestinal and liver cholesterol synthesis in mice, which could potentially lead to a partial attenuation of LDL-C lowering [26,34,44]. Thus, reducing cholesterol absorption with ezetimibe and reducing cholesterol synthesis with statins provide complementary mechanisms of action.…”

“…This reduction in cholesterol delivered to the liver results in a compensatory upregulation of hepatic LDL receptors, thereby enhancing LDL-C clearance and lowering plasma levels of LDL-C (FIGURE 6) [32][33][34]. In monkeys fed a high-fat, highcholesterol diet, ezetimibe treatment substantially reduced the cholesterol ester content of postprandial chylomicrons but had no effect upon the levels of ApoB-48 (the major structural protein of intestinally derived lipoprotein particles), indicating that ezetimibe depleted cholesterol from chylomicrons without reducing the number of chylomicron particles [31].…”

Insig Proteins Mediate Feedback Inhibition of Cholesterol Synthesis in the Intestine

“…We hypothesized that ezetimibe blocks Insig action by lowering ER cholesterol. To test this hypothesis, we fed control and Vil-Insig ؊ mice a diet containing 0.01% ezetimibe, a dose that blocks ϳ90% of lumenal cholesterol absorption (36) (Fig. 7).…”