Abstract
Interruption of enterohepatic circulation (EHC) of bile salts in several species is known to cause a significant decrease in plasma concentrations of low density lipoprotein (LDL) cholesterol, but to have little effect on high density lipoprotein (HDL) cholesterol. The present study, for the first time, demonstrates that partial interruption of EHC dramatically reduces both plasma LDL and HDL cholesterol concentrations in cattle. Five adult Holstein cows were surgically altered to allow controlled portions of bile flow to be diverted from the body. The animals were fed a low-fat, cholesterol-free diet. In two experiments, bile was diverted at 50% and 22% of total flow rates. By day 8 of diversion, both rates reduced mean plasma cholesterol from baseline (85 mg/dl) to about 8 and 18 mg/dl, respectively. Cholesterol was reduced in equal proportions in all lipoprotein fractions. In addition, plasma concentrations of triglycerides and phospholipids were also dramatically reduced. All of these plasma lipids returned to baseline within 1 week after restoration of bile flow. To determine the hepatic response to bile diversion, liver cholesterol concentrations, cholesterol synthesis rates, and LDL receptor-binding activities were determined in biopsy samples. In response to bile diversion, hepatic cholesteryl esters were markedly depleted while hepatic cholesterol synthesis rates were increased by more than 10-fold. Nevertheless, because the basal cholesterol synthesis rate was so low, it was estimated that the increase in synthesis would have supplied no more than 5% of the sterols depleted during bile diversion (1.2 vs. 25 mmol/day). LDL receptor-binding activity was significantly elevated, suggesting an increased uptake of plasma lipoprotein cholesterol by the liver. These results suggest that the unique sensitivity of bovine plasma cholesterol to enterohepatic circulation interruption might occur as a result of the inherently low rate of hepatic cholesterol synthesis in cattle. This hypocholesterolemic model might serve as an interesting tool for the study of factors regulating plasma HDL cholesterol.
Highlights
Interruption of enterohepatic circulation (EHC)of bile salts in several species is known to cause a significant decrease in plasma concentrations of low density lipoprotein (LDL) cholesterol, but to have little effect on high density lipoprotein (HDL)cholesterol.The present study, for the first time, demonstrates that partial interruption of EHC dramatically reduces both plasma LDL and HDL cholesterol concentrations in cattle
The results (Fig.10) show that, by day 14 of bile diversion, liver LDL receptor-binding activity was increased by 40% (P< 0.001)as compared to precannulation and post-cannulation control samples, while there was no change in the binding activity between samples taken at the two control times (Fig. 10)
The role of EHC of bile acids in determining cholesterol homeostasis and the effects of its interruption on cholesterol metabolism have been studied in humans and in a number of other animal species [6,7,8,9,10,11,12]
Summary
Materials [3H]water(100 mCi/mmol) and sodium [1251]iodide (carrier free, pH 7-11) were purchased from New England Nuclear Corp. (Boston, MA). Cholesterol synthesis rate was determined in liver tissues and intestinal mucosal samples by measuring the incorporation rate of tritium from [3H]H20 into digitonin-precipitable sterols (DPS) as described by Andersen and Dietschy [21].Immediately after collection, intestinal mucosal scrapings or thin liver slices (approximate 150 mg) were placed in screw-capped 20-ml glass vials containing 5 mCi of [3H]H20 in 1 ml of MEM under an atmosphere of 95% 0 2 4 % Con. The vials were incubated for 2 h at 37°C in a metabolic shaker or at 0°C in an ice bath. LDL receptor-binding activities of the tissues were determined by measuring heparin-sensitivebinding of lz5I-1abeledLDL to the liver homogenate as described [29].Fifty milligrams of homogenate protein was incubated on ice for 2 h in 150pl of buffer B (NaC1,lOOmM; CaC12, 1 mM; BSA 20 mg/ml; Tris-HC1,50mM, pH 7.5).
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