Micellar theory of biliary cholesterol excretion

Hardison, W. G.; Apter, JT

doi:10.1152/ajplegacy.1972.222.1.61

Cited by 134 publications

(78 citation statements)

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“…Indeed, the present study reaffirms the close association between bile salt secretion and the resultant bile composition (9,48). At This improvement clearly results from an increase in bile salt and phospholipid secretion, rather than any effect on cholesterol.…”

Section: Discussionsupporting

confidence: 84%

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Biliary lipid secretion in cholesterol gallstone disease. The effect of cholecystectomy and obesity.

Shaffer¹,

Small²

1977

J. Clin. Invest.

320

118

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Section: Discussionsupporting

confidence: 84%

“…The reduced bile salt pool, which has been found in patients with cholesterol gallstones, has been assumed to cycle at a normal rate and result in a decreased bile salt secretion rate (5,6). Phospholipid secretion, which depends on bile salt secretion (7)(8)(9), presumably would also be reduced. The …”

mentioning

confidence: 99%

Biliary lipid secretion in cholesterol gallstone disease. The effect of cholecystectomy and obesity.

Shaffer¹,

Small²

1977

J. Clin. Invest.

320

118

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“…This possibility had to be considered, since in rats with a chronic bile drainage newly made cholesterol is a major substrate for bile acid formation (47-49) and ketoconazole blocks cholesterol synthesis at the level of 14a-demethylation (2, 3). On the other hand, it is known that, especially at low bile acid excretion rates, there is a strong correlation between biliary cholesterol and bile acid excretion (50,51), and that cholesterol excretion in the rat does not critically depend on the rate of hepatic cholesterogenesis (52). In addition, we demonstrated that conversion of labeled cholesterol into bile acids is almost complete and inhibited by ketoconazole ( Fig.…”

Section: Discussionmentioning

confidence: 99%

Ketoconazole blocks bile acid synthesis in hepatocyte monolayer cultures and in vivo in rat by inhibiting cholesterol 7 alpha-hydroxylase.

Princen¹,

Huijsmans²,

Kuipers³

et al. 1986

J. Clin. Invest.

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In cultured hepatocytes conversion of 14-4Cicholesterol into bile acids was dose dependently reduced by the antimycotic drug ketoconazole, giving half-maximal inhibition at 10 jM ketoconazole in rat hepatocytes and at 1 jiM in human hepatocytes. No change was observed in the ratio of produced cholic, #t-muricholic, and chenodeoxycholic acid with increasing amounts of the drug.Conversion of 14-'4Cj7a-hydroxycholesterol, an intermediate of bile acid pathway, to bile acids was not affected by ketoconazole. These results together with kinetic studies with rat liver microsomes, demonstrating noncompetitive inhibition (Ki = OA pM), indicate that cholesterol 7a-hydroxylase is the main site of inhibition.In bile-diverted rats a single dose of ketoconazole (50 mg/ kg) dramatically impaired bile flow and biliary bile acid output (92% inhibition). A similar blockade was observed using 14-

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“…Thus, the expression of CYP7A1 indirectly regulates the expression of low density lipoprotein receptors (22,23). Bile acids, which are the end products of the CYP7A1 reaction, stimulate the secretion of phospholipids and cholesterol into bile (24). Thus, the relative expression levels of MTP and CYP7A1 by individual hepatic parenchymal cells are important determinants of whether phospholipids and cholesterol are targeted into plasma (lipoproteins) or bile (biliary lipids).…”

mentioning

confidence: 99%

ARP-1/COUP-TF II Determines Hepatoma Phenotype by Acting as Both a Transcriptional Repressor of Microsomal Triglyceride Transfer Protein and an Inducer of CYP7A1

Kang

Spann

Hui

et al. 2003

Journal of Biological Chemistry

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Individual liver cells, distinguished by their anatomical localization within the portal triad and their relative expression of genes, allow the liver to provide diverse anabolic and catabolic functions. Hepatocytes localized near the portal vein express high levels of lipogenic (1) and gluconeogenic (2) enzymes, whereas those localized near the central vein express high levels of catabolic (CYP7A1) (3, 4) and glycolytic (2) enzymes. Environmental differences caused by hormonal, nutritional, and xenobiotic variations in portal versus central blood result in zonal distinctions in the gene expression of transcription factors within the hepatic acinus (5). The molecular mechanisms responsible for the distinct subsets of genes expressed by individual liver cells remain unknown. We have derived and characterized stable lines of rat hepatoma cells in order to identify the molecular mechanisms responsible for the phenotypic expression of the anabolic lipoprotein assembly pathway regulated by microsomal triglyceride transfer protein (MTP) 1 and the catabolic pathway through which cholesterol is converted into bile acids by the rate-limiting enzyme CYP7A1.The liver is the major site for both the production of plasma lipoproteins and their uptake from plasma and catabolism (reviewed in Ref. 6). The production of apolipoprotein B (apoB)-containing lipoproteins by the liver is mainly regulated by the relative amount of de novo synthesized apoB that is translocated into the endoplasmic reticulum and assembled into a secretion-competent lipoprotein particle (7-10). MTP, an intraluminal protein in the endoplasmic reticulum (11), plays an important role in regulating the assembly and secretion of apoB-containing lipoproteins (12-16). In humans, the loss of MTP function blocks the production of apoB-containing lipoproteins by both the intestine and the liver (11). On the other hand, the catabolic bile acid biosynthetic pathway, regulated by CYP7A1, is the major route through which hepatic (and total body) cholesterol homeostasis is maintained (17-20). Hepatic cholesterol levels indirectly regulate the expression of low density lipoprotein receptors via changes in serum response element (SRE)-binding proteins (21). Thus, the expression of CYP7A1 indirectly regulates the expression of low density lipoprotein receptors (22,23). Bile acids, which are the end products of the CYP7A1 reaction, stimulate the secretion of phospholipids and cholesterol into bile (24). Thus, the relative expression levels of MTP and CYP7A1 by individual hepatic parenchymal cells are important determinants of whether phospholipids and cholesterol are targeted into plasma (lipoproteins) or bile (biliary lipids).We have isolated stable cell clones from rat hepatoma cells as

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Micellar theory of biliary cholesterol excretion

Cited by 134 publications

References 0 publications

Biliary lipid secretion in cholesterol gallstone disease. The effect of cholecystectomy and obesity.

Biliary lipid secretion in cholesterol gallstone disease. The effect of cholecystectomy and obesity.

Ketoconazole blocks bile acid synthesis in hepatocyte monolayer cultures and in vivo in rat by inhibiting cholesterol 7 alpha-hydroxylase.

ARP-1/COUP-TF II Determines Hepatoma Phenotype by Acting as Both a Transcriptional Repressor of Microsomal Triglyceride Transfer Protein and an Inducer of CYP7A1

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