MODULATION OF INTRAHEPATIC CHOLESTEROL TRAFFICKING - EVIDENCE BY IN-VIVO ANTISENSE TREATMENT FOR THE INVOLVEMENT OF STEROL CARRIER PROTEIN-2 IN NEWLY SYNTHESIZED CHOLESTEROL TRANSPORT INTO RAT BILE

Biliary cholesterol represents one of the two major excretory pathways for sterol elimination from the body and plays a central role in chol esterol gallstone formation. Biliary cholesterol originates from a pre cursor pool of preformed and newly synthesized free cholesterol. Altho ugh it has been suggested that newly synthesized and preformed biliary cholesterol are secreted by independent pathways, the specific cellul ar and molecular mechanisms are unknown. We used male Wistar rats to s tudy the time-course of the appearance of newly synthesized cholestero l, phosphatidylcholine and protein into bile. The specific role of ste rol carrier protein-2 (SCP-2) in the transport of newly synthesized bi liary cholesterol was evaluated by an in vivo antisense oligonucleotid e approach. In contrast to [C-14]phosphatidylcholine and [S-35]protein s, the time-course of [C-14]cholesterol appearance into bile was rapid , and microtubule- and Golgi-independent. In vivo SCP-2 antisense trea tment reduced and delayed the appearance of biliary [C-14]cholesterol. Furthermore, hepatic SCP-2 expression increased more than 3-fold over control values in rats that had been treated with diosgenin to increa se biliary secretion of newly synthesized cholesterol. These results s uggest that SCP-2 is necessary for the rapid transport of newly synthe sized cholesterol into bile and that hepatocytes can induce SCP-2 expr ession according to the rate of biliary secretion of newly synthesized cholesterol.