Cholesterol kinetics in subjects with bile fistula. Positive relationship between size of the bile acid precursor pool and bile acid synthetic rate.

Abstract

IntroductionOur aim was to identify and quantitate cholesterol pools and transport pathways in blood and liver. By studying bile fistula subjects, using several types of isotopic preparations, simultaneous labeling of separate cholesterol pools and sampling all components of blood and bile at frequent intervals, we developed a comprehensive multicompartmental model for cholesterol within the rapidly miscible pool. Data in six components (bile acids, esterified cholesterol in whole plasma, and free cholesterol in blood cells, bile, a lipoproteins, and ,B lipoproteins) were modeled simultaneously with the SAAM program. The analysis revealed extensive exchange of free cholesterol between HDL and liver, blood cells, and other tissues. There was net free cholesterol transport from HDL to the liver in most subjects. The major organ that removed esterified cholesterol from blood was the liver. A large portion (4,211 gmol) of total hepatic cholesterol comprised a pool that turned over rapidly (t1/2 of 72 min) by exchanging mainly with plasma HDL and was the major source of bile acids and biliary cholesterol. Only 6% of hepatic newly synthesized cholesterol was used directly for bile acid synthesis: the analysis showed that 94% of newly synthesized cholesterol was partitioned into the large hepatic pool (putative plasma membrane free cholesterol) which exchanged rapidly with plasma lipoproteins. Bile acid synthetic rate correlated directly with the size of the large hepatic pool.In conclusion, hepatic and blood cholesterol pools and transports have been quantitated. HDL plays a central role in free cholesterol exchange/transport between all tissues and plasma. In humans, the metabolically active pool comprises a large portion of total hepatic cholesterol that, in part, regulates bile acid synthesis. (J. Clin. Invest. 1993. 91:923-938.)

A novel approach to measuring macrophage-specific reverse cholesterol transport in vivo in humans

“…Schwartz et al used a similar preparation to study cholesterol metabolic pathways in humans. Their results were consistent with the rapid clearance of the cholesterolalbumin complexes from the blood compartment and subsequent reappearance of the tracer on circulating HDL as free cholesterol (FC), suggesting that this approach may specifically measure the efflux of cholesterol from macrophage cells to HDL as sole acceptor (11)(12)(13)(14).…”

“…We did consider the use of modified LDL particles; however, the GMP preparation of such particles for human use is not straightforward. Our choice to use cholesterol nanoparticles for the assessment of the RCT pathway was driven by the feasibility of their GMP preparation for human use and the existence of supporting data not only from previous animal studies by Nilsson and Zilversmit (10), but also critical from human proof-ofconcept data generated by Schwartz et al (11)(12)(13)(14). Importantly, our data support the concept that the FC bound to albumin in these nanoparticles was taken up before extensively exchanging with red blood cells.…”

“…Because our protocol used a single tracer and did not involve bile sampling, the Schwartz model was modified so that all parameters could be identified with confidence. Previously published results provided estimates of the initial parameters utilized during the fitting process (13,15). FC on HDL can transfer to nonHDL particles, red blood cells, or peripheral tissue cholesterol (a composite of cholesterol from all nonliver tissues, (14) with the addition of a transport pathway from HDL-CE to liver.…”

Identification of a PDZ-domain-containing protein that interacts with the scavenger receptor class B type I

“…It has been shown that HDL cholesterol is a major source of substrate for biliary steroid secretion in both HDL mammals such as rats and low-density lipoprotein mammals such as humans (24). There is also considerable evidence to suggest that cholesterol in the liver is compartmentalized into different functional pools (25), with cholesterol secreted into plasma in very-low-density lipoproteins being derived from a pool that is distinct from the one used for bile acid synthesis (26).…”

Biliary cholesterol hypersecretion in gallstone-susceptible mice is associated with hepatic up-regulation of the high-density lipoprotein receptor SRBI

“…This may in part explain that HDL may contribute to as much as 80% of cholesterol secreted into bile of humans. 53,54 So far, the exact molecular mechanism whereby binding of HDL to SRBI facilitates delivery of cholesteryl esters to the plasma membrane is not resolved. However, because the capacity of the plasma membrane in accommodating cholesteryl esters is limited to ϳ3 mol% with respect to membrane phospholipids, 55 continued selective uptake must involve the rapid removal of cholesteryl esters from the plasma membrane.…”