Multicompartmental Analysis of Cholesterol Metabolism in Man

Abstract

A B S T R A C T The present report has presented the first clear evidence in man for the existence of specific hepatic cholesterol precursor sites associated with the formation and secretion of bile acids and biliary cholesterol. These hepatic compartments derive virtually all their cholesterol from newly synthesized and lipoprotein free cholesterol. The model which is presented was formulated on current concepts of cholesterol metabolism in man and is concerned, at this initial stage, with the elucidation of the bile acid and biliary cholesterol compartments. The complexity of cholesterol metabolism in man necessitated an initial approach that would minimize the number of inputs of cholesterol into the system, allow for the sampling of several cholesterol compartments, and permit the simultaneous labeling of newly synthesized cholesterol and preformed cholesterol. To achieve these objectives, we studied the patient with a total bile fistula. Six patients were administered simultaneously pulse iinjections of labeled mevalonic acid and[14C]cholesterol. The qualitative features ofthe specific activity time course curves after labeled mevalonic acid revealed no precursor-product relationship between bile acid, biliary cholesterol, and plasma free cholesterol. The peak specific activity of the bile acids was reached in approximately 100 min and was higher than the biliary cholesterol, which was higher than the plasma free cholesterol. The plasma free cholesterol specific activity became higher than the other lipids after 12 h and remained higher throughout the period During the model development, the least number of compartments and transport pathways were introduced consistent with a good fit of the data. Of particular importance was the constraint that the model fit the data obtained from both [14C]cholesterol and labeled mevalonic acid. The same parameter values were used to fit the data from both tracers. The fluxes arrived at in the model indicate that 31% and 20%, respectively, of the cholesterol input into the bile acid and biliary cholesterol precursor sites were derived directly from the newly synthesized hepatic cholesterol. The remainder had its origin predominantly from lipoprotein free cholesterol. Plasma esterified cholesterol (as free) made a small contribution (11%) to the bile acid compartment. Similarly, 10% of the biliary cholesterol arose from an unknown hepatic site.The present report has provided the basis for a new procedure for studying in vivo cholesterol metabolism in man. Examination of the derived cholesterol flux rates between the compartments suggests the presence of an important mechanism regulating the partitioning of lipoprotein free cholesterol between the bile acid and biliary cholesterol precursor sites. Aberrations in the proportioning of precursor cholesterol between these sites could be a causative factor precipitating the excessive secretion of biliary cholesterol and the production of lithogenic bile.

Mevalonic acid in human plasma: relationship of concentration and circadian rhythm to cholesterol synthesis rates in man.

“…MVA is cleared from plasma by several routes; none appears to be saturated at physiological concentrations: (i) removal by the kidney, either through resorption and metabolism or by excretion into the urine (18,19), and (ii) removal by conversion to sterols or metabolism to nonsterol products primarily in the liver and intestine (20). There is no suggestion from available evidence that clearance mechanisms would be affected by cholestyramine administration or cholesterol feeding.…”

The synthesis of [14C]SK&F 97426A. A novel bile acid sequestrant

“…This has the effect of increasing bile acid synthesis, from cholesterol, and a consequent reduction of plasma cholesterol levels (ref. 2). SK&F 97426A (10) is a 1% cross linked 1 1-trimethylammonioundecylmethacrylate chloride ethylene glycol dimethacrylate co-polymer BAS under development by SmithKline Beecham for the treatment of hypercholesterolaemia (ref.…”

Evidence for a Common Hepatic Cholesterol Precursor Site for Cholic and Chenodeoxycholic Acid Synthesis in Man

“…Recent studies (1)(2)(3)(4) in the rat and man have provided evidence for the existence of a specific hepatocellular cholesterol compartment associated with the synthesis of bile acids. It has also been suggested (5,6) that both primary bile acids (cholic3 and chenodeoxycholic acids) are derived from this hepatic cholesterol site.…”

“…In addition, although bile acid synthesis is markedly stimulated, the proportion of cholic acid synthesis to chenodeoxycholic acid synthesis is normal. 4 Each patient had a balloon-occludable T tube inserted in the common bile duct during cholecystectomy and choledocholithotomy for gallstone disease. The experiments were carried out 2-4 weeks after surgery, when liver function tests were normal.…”

“…These results provide direct evidence that cholic and chenodeoxycholic acids arise from the same hepatic cholesterol precursor site (compartment) in man, and are in contrast to the findings of Mitropoulos et al (7), who suggested that, in the bile fistula rat, chenodeoxycholic acid may be formed from a compartment of cholesterol other than that from which cholic acid is derived. Isotopic equilibration of labeled, newly synthesized cholesterol throughout the total hepatic cholesterol pool has been shown to take several hours (2)(3)(4). If cholic and chenodeoxycholic acids were derived in part or in toto from separate cholesterol compartments, differences in their specific activities should have been most apparent in the first few hours following the administration of the labeled precursors.…”