Reduction of bovine plasma cholesterol concentration by partial interruption of enterohepatic circulation of bile salts: a novel hypocholesterolemic model.

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.