Role of plasma and liver cholesterol- and lipoprotein-metabolism determinants in LpX formation in the mouse

Cholestasis is characterized by hypercholesterolemia and the appearance of an abnormal lipoprotein, lipoprotein X (LpX), in plasma. The mechanisms responsible for this cholestatic plasma lipid phenotype are not fully understood. We used ATP-binding cassette A1 (ABCA1)(−/−) and scavenger receptor class B type I (SR-BI)(−/−) mice to test the hypothesis that hepatic sinusoidal cholesterol transporters contribute to LpX formation and hypercholesterolemia during cholestasis. Bile-duct ligation (BDL) of both ABCA1(−/−) and SR-BI(−/−) mice, as well as their respective controls, induced a dramatic increase in plasma cholesterol and phospholipid concentrations. Plasma fractionation revealed the presence of LpX in plasma of cholestatic mice, irrespective of their genetic background. We observed that the presence of HDL before cholestasis, a decrease in the activity of LCAT, and an increase in VLDL synthesis were not required for hypercholesterolemia and lipoprotein modifications induced by obstructive cholestasis in mice. In addition, murine cholestasis resulted in increased hepatic cholesterol synthesis that may contribute to the higher plasma free cholesterol levels found during the early hours after BDL. Together these findings indicate that hypercholesterolemia and LpX formation associated with obstructive cholestasis are correlated with an increase in hepatic cholesterol synthesis and are independent of plasma HDL levels, LCAT activity, VLDL synthesis, and ABCA1 and SR-BI expression.