Studies on the Cholesterol Pool as the Precursor of Bile Acids in the Rat

Ogura, Michio; J, Shiga; Yamasaki, Kazumi

doi:10.1093/oxfordjournals.jbchem.a129726

Cited by 39 publications

(14 citation statements)

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“…The contribution of NSC may be exaggerated in the bile fistula patient, since he has low plasma cholesterol levels and increased hepatic cholesterol synthesis. The present data are also in general agreement with studies in the rat which have shown that hepatic NSC is a substrate for bile acid synthesis (13)(14)(15)(16)(17)(18)(19). However, contrary to the findings in the bile fistula rat in which NSC is the major substrate, man with a bile fistula preferentially utilizes cholesterol from the plasma free compartment for bile acid synthesis.…”

Section: Resultssupporting

confidence: 90%

“…Also, the major body cholesterol pool sizes have been estimated from these kinetic data (9,10 Recent studies in the rat (13)(14)(15)(16)(17)(18)(19) have raised questions regarding the present concept of the homogeneity of the plasma-liver cholesterol compartment. In the rat, the preferred substrate for both cholesterol 7a-hydroxylase and the in vivo formation of 7a-hydroxycholesterol has been shown to be newly synthesized cholesterol (NSC) (13)(14)(15)(16)(17)(18)(19). Also, bile acids appear to be derived from a precursor site which turns over much more rapidly than biliary cholesterol (13,15).…”

Section: Introductionmentioning

confidence: 99%

“…However, it was noted that no consistent precursor-product relationship was present between bile acids and biliary cholesterol after the administration of labeled cholesterol, suggesting that these two sterols may not arise from a common hepatic site. In view of this observation and the recent findings (13)(14)(15)(16)(17)(18)(19) in the rat that bile acids arise to a large extent from NSC, it was of interest to examine the possibility that the cholesterol precursor of the bile acids is also heterogeneous in man. Therefore, bile fistula patients without an intervening bile acid pool were administered an iv pulse of labeled mevalonic acid (20).…”

Section: Introductionmentioning

confidence: 99%

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Multicompartmental Analysis of Cholesterol Metabolism in Man

Schwartz¹,

Berman²,

Vlahčevič³

et al. 1978

J. Clin. Invest.

191

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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.

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Section: Resultssupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Multicompartmental Analysis of Cholesterol Metabolism in Man

Schwartz¹,

Berman²,

Vlahčevič³

et al. 1978

J. Clin. Invest.

191

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“…These definitions do not imply a mechanism but are simply related to the origin of the molecules. Bile cholesterol l-U t ton/ Brot-Laroche comes from plasma (9,21), while the intestinal mucosa contains both plasma cholesterol and cholesterol synthesized in situ. With the isotop ic equilibrium method, which we apply exten sively in the study of cholesterol metabolism, we can differentiate between fecal cholesterol from excretion, from external secretion, and from unabsorbed diet cholesterol, and measure their corresponding daily rales (6).…”

mentioning

confidence: 99%

<i>In vivo </i>Plasma Cholesterol Exchanges in the Digestive Tract of the Rat: Effect of <i>L</i>-Thyroxine

Lutton¹,

Brot-Laroche²

1980

Digestion

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Cholesterol exchanges between plasma and digestive organs (stomach, small intestine divided into jejunum and ileum, cecum plus colon) were studied in control and in L-thyroxine-fed rats receiving a constant venous infusion of (³H)-cholesterol for 3 or for 6 h and in unoperated rats by use of the isotopic equilibrium method. In control rats, total cholesterol radioactivity in the walls of stomach, intestine and cecum-colon averaged 0.50% of infused (³H)-cholesterol at the end of 6 h; between 70 and 75% of this radioactivity was located in the intestine. However, the relative transfer rates into these walls, expressed as tissue radioactivity for the same free cholesterol specific activity in the plasma at the moment of sacrifice, are nearly the same when expressed per gram of tissue (walls) or per milligram of DNA in the epithelial cells of the jejunum and the ileum. In thyroxine-fed rats, total cholesterol radioactivity in the walls reached 1.27% of infused (³H)-cholesterol after 6 h, the intestine still containing the major part of radioactivity (80%). The relative cholesterol transfer rates into the walls are unchanged in stomach, ileum and cecum-colon when compared to the controls. But in the jejunum, L-thyroxine causes a twofold increase in plasma cholesterol exchanges through the wall and through the epithelial cell membrane. Moreover, in the epithelial cell of the jejunum, this hormone increases the percentage of plasma cholesterol, as estimated by the isotopic equilibrium method. Plasma cholesterol radioactivity enters the lumen mainly through the jejunal mucosa. L-Thyroxine strongly enhances jejunal excretion of plasma cholesterol explaining the twofold increase of fecal cholesterol excretion.

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“…The majority of the information to date indicates that the initial reaction of the metabolism of cholesterol into bile acids in the liver is the incorpora tion of a hydroxyl group at the 7 a-position of the ring system of cholesterol by the enzyme, 7 «-hydroxylase. The substrate for 7 ahydroxylase is free, unesterified cholesterol and not cholesterol esters (Ogura et al, 1971). Newly synthesized cholesterol is preferred over free plasma cholesterol (Mitropoulos et al, 1974;Schwartz èt al., 1975).…”

Section: Enterohepatic Circulation Of Bile Saltsmentioning

confidence: 99%

Effect of dietary fat on cholesterol absorption, synthesis and transport in the preruminant calf

Davis

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Studies on the Cholesterol Pool as the Precursor of Bile Acids in the Rat

Cited by 39 publications

References 0 publications

Multicompartmental Analysis of Cholesterol Metabolism in Man

Multicompartmental Analysis of Cholesterol Metabolism in Man

<i>In vivo </i>Plasma Cholesterol Exchanges in the Digestive Tract of the Rat: Effect of <i>L</i>-Thyroxine

Effect of dietary fat on cholesterol absorption, synthesis and transport in the preruminant calf

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