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Partial characterization of regulation of biliary lecithin hydrophobicity: association with organic anion-induced solute cholestasis in rats.

ABSTRACT: We examined the effects of the depletion of bile salts and of the intravenous infusion of sodium taurocholate (STC) with or without bromosulphophthalein (BSP) in rats on the biliary secretion of lipids to clarify the regulatory mechanism(s). Each rat was equipped with a bile-duct cannula to collect bile. After the endogenous bile salt pool was depleted, STC was infused at a constant rate (160 nmol/min per 100 g body wt.) with or without BSP (50, 100, or 150 nmol/min per 100 g body wt.). BSP reduced the biliary secretion of cholesterol and phospholipids dose-dependently without affecting the secretion of bile salts (uncoupling phenomenon). Compared with the physiological and STC-infused condition, the biliary cholesterol/phospholipid ratio and saturated/unsaturated fatty acid ratio increased under the bile salts depletion and uncoupling phenomenon. Data indicate that the hydrophobicity of biliary lecithin increases with a decrease in the bile salt micelle capacity to induce biliary lipid secretion, resulting in a higher packing density of biliary vesicle. The cholesterol-holding capacity of the biliary vesicle is therefore enhanced during the depletion of bile salts and the uncoupling phenomenon.

SUBMITTER: Miura H

PROVIDER: S-EPMC1136184 | biostudies-other | 1995 Dec

REPOSITORIES: biostudies-other

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Project description:Background & aimsBile acid transporters maintain bile acid homeostasis. Little is known about the functions of some transporters in cholestasis or their regulatory mechanism. We investigated the hepatic expression of solute carrier organic anion transporter family member 3A1 (SLCO3A1, also called OATP3A1) and assessed its functions during development of cholestasis.MethodsWe measured levels of OATP3A1 protein and messenger RNA and localized the protein in liver tissues from 22 patients with cholestasis and 21 patients without cholestasis, using real-time quantitative polymerase chain reaction, immunoblot, and immunofluorescence analyses. We performed experiments with Slco3a1-knockout and C57BL/6J (control) mice. Mice and Sprague-Dawley rats underwent bile duct ligation (BDL) or a sham operation. Some mice were placed on a 1% cholic acid (CA) diet to induce cholestasis or on a control diet. Serum and liver tissues were collected and analyzed; hepatic levels of bile acids and 7-α-C4 were measured using liquid chromatography/mass spectrometry. Human primary hepatocytes and hepatoma (PLC/PRF/5) cell lines were used to study mechanisms that regulate OATP3A1 expression and transport.ResultsHepatic levels of OATP3A1 messenger RNA and protein were significantly increased in liver tissues from patients with cholestasis and from rodents with BDL or 1% CA diet-induced cholestasis. Levels of fibroblast growth factor 19 (FGF19, FGF15 in rodents) were also increased in liver tissues from patients and rodents with cholestasis. FGF19 signaling activated the Sp1 transcription factor and nuclear factor κB to increase expression of OATP3A1 in hepatocytes; we found binding sites for these factors in the SLCO3A1 promoter. Slco3a1-knockout mice had shorter survival times and increased hepatic levels of bile acid, and they developed more liver injury after the 1% CA diet or BDL than control mice. In hepatoma cell lines, we found OATP3A1 to take prostaglandin E2 and thyroxine into cells and efflux bile acids.ConclusionsWe found levels of OATP3A1 to be increased in cholestatic liver tissues from patients and rodents compared with healthy liver tissues. We show that OATP3A1 functions as a bile acid efflux transporter that is up-regulated as an adaptive response to cholestasis.

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Partial characterization of regulation of biliary lecithin hydrophobicity: association with organic anion-induced solute cholestasis in rats.

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