Accumulation of cholestatic lipoproteins in ANIT-treated human apolipoprotein A-I transgenic rats is diminished through dose-dependent apolipoproteinA-I activation of LCAT

Administration of alpha-naphthylisothiocyanate (ANIT) to rats induces chang es to plasma lipids consistent with cholestasis, We have previously shown ( J. Lipid Res. 37 (1996) 1086) that animals treated with ANIT accumulate lar ge amounts of free cholesterol (FC) and phospholipid (PL)-rich cholestatic lipoproteins in the LDL density range by 48 h. This lipid was cleared by 12 0 h through apparent movement into HDL with concomitant cholesteryl ester ( CE) production. It was hypothesised that the clearance was mediated through the movement of the PL and FC into apolipoprotein A-I (apo A-I) containing lipoproteins followed by LCAT esterification to form CE. To test this hypo thesis, rats overexpressing various amounts of human ape A-I (TgR[HuAI] rat s) were treated with ANIT (100 mg/kg) and the effect of plasma apo A-I conc entration on plasma lipids and lipoprotein distribution was examined. In un treated TgR[HuAI] rats, human apo A-I levels were strongly correlated to pl asma PL (r(2) = 0.94), FC (r(2) = 0.93) and CE (r(2) = 0.90), whereas in AN IT-treated TgR[HuAI] rats, human apo A-I levels were most strongly correlat ed to CE levels (r(2) = 0.80) and an increased CE/FC ratio (r(2) = 0.62) an d the movement of cholestatic lipid in the LDL to HDL. Since LCAT activity was not affected by ANIT treatment, these results demonstrate that the abil ity of LCAT to esterify the plasma FC present in cholestatic liver disease is limited by in vivo apo A-I activation of the cholestatic lipid and not b y the catalytic capacity of LCAT. (C) 2000 Elsevier Science B.V. All rights reserved.