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

Background & Aims: Because apolipoprotein E (apoE) is a key cholesterol tra nsport 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 th is hypothesis, we studied biliary lipid secretion and gallstone formation i n apoE-deficient mice fed cholesterol-rich diets. Methods: Bile lipid outpu ts and gallstone sequence events were analyzed in apoE-deficient mice fed a high-cholesterol diet or a lithogenic diet compared with control animals. Results: A high-cholesterol diet increased biliary cholesterol secretion an d gallbladder bile cholesterol concentration in wild-type mice; the increas e in bile cholesterol secretion was significantly attenuated in apoE-defici ent mice. ApoE knockout mice fed a high-cholesterol lithogenic diet had a m arkedly lower frequency of gallbladder bile cholesterol crystal and gallsto ne formation than wild-type mice, which was most likely a result of the dec reased cholesterol saturation index found in gallbladder bile of apoE-defic ient mice. Conclusions: These results show that apoE expression is an impor tant factor for regulating both biliary secretion of diet-derived cholester ol as well as diet-induced cholesterol gallstone formation in mice.