Impaired biliary cholesterol secretion and decreased gallstone formation in apolipoprotein E-deficient mice fed a high-cholesterol diet.

Abstract

Because apolipoprotein E (apoE) is a key cholesterol transport molecule involved in the hepatic uptake of chylomicron cholesterol, it may play a critical role in controlling bile cholesterol elimination and cholesterol gallstone formation induced by dietary cholesterol. To test this hypothesis, we studied biliary lipid secretion and gallstone formation in apoE-deficient mice fed cholesterol-rich diets. Bile lipid outputs and gallstone sequence events were analyzed in apoE-deficient mice fed a high-cholesterol diet or a lithogenic diet compared with control animals. A high-cholesterol diet increased biliary cholesterol secretion and gallbladder bile cholesterol concentration in wild-type mice; the increase in bile cholesterol secretion was significantly attenuated in apoE-deficient mice. ApoE knockout mice fed a high-cholesterol lithogenic diet had a markedly lower frequency of gallbladder bile cholesterol crystal and gallstone formation than wild-type mice, which was most likely a result of the decreased cholesterol saturation index found in gallbladder bile of apoE-deficient mice. These results show that apoE expression is an important factor for regulating both biliary secretion of diet-derived cholesterol as well as diet-induced cholesterol gallstone formation in mice.