Effect of ursodeoxycholic acid on hepatic LDL binding and uptake in dietary hypercholesterolemic hamsters

Administration of ursodeoxycholic acid (UDCA) has been shown to decrease se rum total and low density lipoprotein (LDL) cholesterol in hypercholesterol emic patients with primary biliary cirrhosis. Results of previous studies p rompted us to postulate that the cholesterol-lowering effect of UDCA may be due, at least in part, to a direct increment in hepatic LDL receptor bindi ng [Bouscarel ct al., Biochem J, 1991;280:589; Bouscarel et al., Lipids 199 5;30:607]. The aim of the present investigation was to determine the abilit y of UDCA to enhance hepatocellular LDL receptor recruitment, as determined by its effect in vivo on LDL uptake, and its effect in vitro on LDL bindin g, under conditions of moderately elevated serum cholesterol. Study groups consisted of male golden Syrian hamsters fed either a standard chow diet (c ontrol), a 0.15% cholesterol-containing diet, or a 0.15% cholesterol-contai ning diet supplemented with either 0.1% UDCA, or 0.1% chenodeoxycholic acid (CDCA). Cholesterol feeding increased (P < 0.01) total serum cholesterol b y 44%, and was associated with a 10-fold accumulation of cholesteryl esters in the liver (P < 0.01). In vivo, hepatic uptake of [U-C-14]sucrose-labele d hamster LDL was increased (P < 0.05) to a level of 454 +/- 101 <mu>l in a nimals fed a cholesterol-containing diet supplemented with UDCA, compared t o that either without UDCA (337 +/- 56 mul), or with CDCA (240 +/- 49 mul). The hepatic uptake of [U-C-14]sucrose-labeled methylated human LDL, a mark er of LDL receptor-independent LDL uptake, was unaffected by bile acid feed ing. In vitro, specific binding of [I-125]hamster LDL to isolated hepatocyt es was determined at 4 degreesC, in presence and absence of 700 mu mol/l UD CA. The K-D ranged from 25 to 31 mug/ml, and was not affected by either cho lesterol feeding or UDCA. In the presence of UDCA, the B-max was increased by 19% (P < 0.05) in cells isolated from control animals and by 29% (P < 0. 01) in cells isolated from hamsters fed a cholesterol-supplemented diet. In conclusion, in dietary hypercholesterolemic hamsters, both chronic in-vivo and acute in-vitro treatments with UDCA resulted in restoration of hepatic LDL binding and uptake to levels observed in control hamsters. (C) 2000 El sevier Science Ireland Ltd. All rights reserved.