Regulation of apolipoprotein B secretion in hepatocytes from Watanabe heritable hyperlipidemic rabbit, an animal model for familial hypercholesterolemia

Abstract

Regulation of apolipoprotein B-100 (apo B) secretion in the liver in familial hypercholesterolemia (FH) remains largely unknown. In a previous study, we developed a rabbit hepatocyte culture system and investigated a cellular mechanism which regulates apo B secretion from hepatocytes in response to cellular cholesteryl ester contents [18]. Using this system, in the present study, we investigated regulation of apo B secretion in hepatocytes from the Watanabe heritable hyperlipidemic (WHHL) rabbit, an animal model for FH. Incubation with low density lipoproteins (LDL) at concentrations of 50 or 200 μg/ml, which increased both cellular cholesteryl ester and apo B secretion significantly in normal rabbit hepatocytes, did not cause such increases in WHHL rabbit hepatocytes. However, when WHHL rabbit hepatocytes were incubated with LDL at a concentration of 500 μg/ml, a significant increase in cellular cholesteryl ester and apo B secretion was observed. The effect of the increase in cellular level of cholesteryl ester upon apo B secretion in WHHL rabbit hepatocytes was compatible with that in normal rabbit hepatocytes. Indeed, when WHHL rabbit hepatocytes were incubated with LDL at 1680 μg/ml, a concentration comparable to that of WHHL rabbit plasma, the amount of LDL degradation, cellular cholesteryl ester level, and level of apo B secretion were the same as those in normal rabbit hepatocytes that were incubated with LDL at 160 μg/ml, a concentration comparable to that of normal rabbit plasma. In summary, our present study suggests that, at a steady state with such a high plasma concentration of LDL, the hepatic cholesterol content in WHHL rabbits could be set at the same level as in normal rabbits. It was also shown that cellular cholesteryl ester contents had the same regulatory effect on apo B secretion in WHHL rabbit hepatocytes as in normal rabbit hepatocytes. Therefore, we conclude that in the presence of the genetic defect of the LDL receptor, plasma cholesterol in WHHL rabbit is maintained at a concentration such that apo B secretion is similar to that in normal rabbit.