Abnormal lipoprotein metabolism in animal models of intrahepatic cholestasis induced by alpha-naphthylisothiocyanate.
Date
1997
Authors
Chisholm, Jeffrey W.
Journal Title
Journal ISSN
Volume Title
Publisher
Dalhousie University
Abstract
Description
The $\alpha$-naphthylisothiocyanate (ANIT) treated rat and mouse were evaluated as models of abnormal lipoprotein metabolism in familial lecithin: cholesterol acyltransferase (LCAT) deficiency and cholestatic liver disease.
In the rat, alterations in plasma lipoprotein composition were studied from 0 to 120 h. By 48 h, plasma free cholesterol (FC), cholesteryl ester (CE) and phospholipid (PL) were increased 9.4, 2.9 and 6.1 fold with a concomitant reduction in the CE/FC ratio. LCAT and lipoprotein lipase (LPL) activities were near normal while hepatic triacylglycerol lipase (HTGL) was decreased. Elevated FC and PL were primarily associated with an increase in lipoproteins within the low density lipoprotein (LDL) density range that contained apolipoprotein (apo) A-I and E. The composition of these lipoproteins was consistent with the presence of abnormal lipoprotein-X-like vesicles. By 120 h, vesicles within the LDL density range were cleared through apparent movement of PL and FC into high density lipoproteins (HDL). In ANIT-treated human apo A-I transgenic rats, a positive correlation between plasma apo A-I levels, CE and a reduction in the accumulation PL and FC-rich lipoproteins within the LDL density range was demonstrated.
These results indicate that the ANIT-treated rat is a reversible model of abnormal lipoprotein metabolism in transient intrahepatic cholestasis where LCAT is functional and that the clearance of PL and FC-rich LDL lipoproteins is limited by the apo A-I mediated generation of LCAT substrate HDL and not LCAT activity.
In the ANIT-treated mouse, plasma PL and FC concentrations at 48, 72 and 168 h were increased 10, 11, 13 and 17, 20, 45 fold respectively. Elevations in these lipids were followed by very low CE levels, CE/FC ratio and LCAT activity (48 h). As in the rat, the ratio of FC and PL within the LDL density region was consistent with the presence of vesicles. These results suggest that the ANIT-treated mouse may be a useful model for studying the abnormal lipoproteins of LCAT deficiency and intrahepatic cholestasis.
Thesis (Ph.D.)--Dalhousie University (Canada), 1997.
In the rat, alterations in plasma lipoprotein composition were studied from 0 to 120 h. By 48 h, plasma free cholesterol (FC), cholesteryl ester (CE) and phospholipid (PL) were increased 9.4, 2.9 and 6.1 fold with a concomitant reduction in the CE/FC ratio. LCAT and lipoprotein lipase (LPL) activities were near normal while hepatic triacylglycerol lipase (HTGL) was decreased. Elevated FC and PL were primarily associated with an increase in lipoproteins within the low density lipoprotein (LDL) density range that contained apolipoprotein (apo) A-I and E. The composition of these lipoproteins was consistent with the presence of abnormal lipoprotein-X-like vesicles. By 120 h, vesicles within the LDL density range were cleared through apparent movement of PL and FC into high density lipoproteins (HDL). In ANIT-treated human apo A-I transgenic rats, a positive correlation between plasma apo A-I levels, CE and a reduction in the accumulation PL and FC-rich lipoproteins within the LDL density range was demonstrated.
These results indicate that the ANIT-treated rat is a reversible model of abnormal lipoprotein metabolism in transient intrahepatic cholestasis where LCAT is functional and that the clearance of PL and FC-rich LDL lipoproteins is limited by the apo A-I mediated generation of LCAT substrate HDL and not LCAT activity.
In the ANIT-treated mouse, plasma PL and FC concentrations at 48, 72 and 168 h were increased 10, 11, 13 and 17, 20, 45 fold respectively. Elevations in these lipids were followed by very low CE levels, CE/FC ratio and LCAT activity (48 h). As in the rat, the ratio of FC and PL within the LDL density region was consistent with the presence of vesicles. These results suggest that the ANIT-treated mouse may be a useful model for studying the abnormal lipoproteins of LCAT deficiency and intrahepatic cholestasis.
Thesis (Ph.D.)--Dalhousie University (Canada), 1997.
Keywords
Biology, Animal Physiology., Chemistry, Biochemistry., Health Sciences, Pathology.