Comparison of taurocholate accumulation in cultured hepatocytes of pig, rat and man

Kwekkeboom, Jaap; Princen, H.M.G.; Voorthuizen, E.M. van; Meijer, Piet; Kempen, H.J.M.

doi:10.1016/0006-291x(89)92355-3

Cited by 25 publications

(16 citation statements)

References 23 publications

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“…Moreover, several groups of investigators were unable to demonstrate any direct inhibitory effect of bile salts on bile salt synthesis in hepatocyte suspensions or cultures (6,7,32). Although more recent studies in cultured hepatocytes suggest that hydrophobic bile salts may suppress 7␣-hydroxylase expression and regulate 7␣-hydroxylase promoter activity (33)(34)(35)(36)(37), this seems to occur only at hepatocyte bile salt concentrations greatly exceeding those found in vivo (38), raising questions about the physiologic relevance of these findings. Recently, Pandak et al (12) reported that intraduodenally administered taurocholate exerted negative feedback inhibition on hepatic 7␣-hydroxylase expression in the rat, whereas equimolar quantities of intravenously administered taurocholate had no effect.…”

Section: Discussionmentioning

confidence: 99%

Feedback Regulation of Hepatic 7α-Hydroxylase Expression by Bile Salts in the Hamster

Spady

Cuthbert

Willard

et al. 1996

Journal of Biological Chemistry

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Hepatic 7␣-hydroxylase activity appears to be regulated at the transcriptional level by the quantity of bile salts fluxing through the enterohepatic circulation. Whether bile salts directly suppress 7␣-hydroxylase expression at the level of the hepatocyte or do so indirectly by promoting the release or absorption of an intestinal factor has not been resolved. We have investigated the ability of primary bile salts to suppress hepatic 7␣-hydroxylase expression in bile-diverted hamsters. Biliary diversion was accompanied by derepression of both hepatic 7␣-hydroxylase activity (4 -5-fold) and bile salt secretion (ϳ3-fold). Derepression of hepatic 7␣-hydroxylase expression could be prevented by several interventions that increase the availability of bile salts within the hepatocyte including 1) overexpression of an exogenous 7␣-hydroxylase gene by adenovirus-mediated gene transfer, 2) obstruction of the common bile duct, and 3) intravenous infusions of taurocholate. In contrast, none of these interventions prevented derepression of hepatic cholesterol synthesis or significantly down-regulated hepatic low density lipoprotein receptor expression over the relatively short time course (24 h) of these studies. Together, these data indicate that primary bile salts contribute to the regulation of bile salt synthesis through feedback repression of 7␣-hydroxylase expression at the level of the hepatocyte.Conversion of cholesterol to bile salts is the principal regulated pathway whereby cholesterol is eliminated from the body. The first and rate-limiting step in this pathway is catalyzed by hepatic cholesterol 7␣-hydroxylase (1). Hepatic 7␣-hydroxylase activity appears to be regulated at the transcriptional level by the quantity of bile salts fluxing through the enterohepatic circulation (2, 3). Thus, interventions that accelerate bile salt loss from the enterohepatic circulation (thereby reducing bile salt pool size) lead to derepression of hepatic 7␣-hydroxylase expression and enhanced bile salt synthesis. Conversely, expansion of the enterohepatic pool of bile salts leads to suppression of 7␣-hydroxylase activity and reduced rates of bile salt formation.How bile salts fluxing through the enterohepatic circulation regulate the expression of hepatic 7␣-hydroxylase remains unclear. In the bile-diverted rat, depletion of the enterohepatic pool of bile salts leads to derepression of hepatic 7␣-hydroxylase activity and an increase in the rate of bile salt synthesis, effects that can be prevented by the intraduodenal administration of bile salts (4, 5). The conventional interpretation of these experiments is that the flux of bile salts through the hepatocyte (or, more likely, the concentration of bile salts within the hepatocyte) is being sensed, resulting in feedback repression of the rate-limiting enzyme in the bile salt biosynthetic pathway. However, early studies using hepatocyte suspensions or cultures failed to demonstrate any direct regulatory effect of exogenous bile salts on the secretion of bile salts into the media (6, ...

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Section: Discussionmentioning

confidence: 99%

Feedback Regulation of Hepatic 7α-Hydroxylase Expression by Bile Salts in the Hamster

Spady

Cuthbert

Willard

et al. 1996

Journal of Biological Chemistry

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“…35 Further-more, the cells could synthesize and secrete VLDL, LDL, HDL (with VLDL as the major species, namely 68%±9%); apo B, apo A-l, apo A-ll, apo E, apo C-ll, 36 albumin, and plasminogen activator inhibitor 1. 37 Also the transport and metabolism of thyroid hormones was qualitatively comparable to these processes in rat hepatocytes.…”

Section: Isolation and Culturing Of Human Hepatocytesmentioning

confidence: 99%

“…Up-regulation of the HDL binding sites can be induced by loading the cells with cholesterol/ albumin complexes 46 or acetylated low density lipoprotein (LDL). 35 In a manner similar to peripheral cells, a high affinity binding site for HDL has been identified on hepatocytes of various species 7 - 15 and on liver membranes, 16 -19 including human liver membranes. 20 Recently, we characterized the high affinity recognition sites for HDL on parenchymal, endothelial, and Kupffer cells from rat liver in vitro.…”

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confidence: 99%

Characterization in vitro of interaction of human apolipoprotein E-free high density lipoprotein with human hepatocytes.

Schouten

Kleinherenbrink-Stins

Brouwer

et al. 1990

Arteriosclerosis

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Characterization of the interaction of iodinated apolipoprotein (apo) E-free high density lipoprotein (HDL) with cultured human hepatocytes provides evidence for a saturable, Ca 2+ -independent, high affinity binding site with an apparent k m value of 20 fig/ml of apolipoprotein. Nitrated HDL and low density lipoprotein (LDL) did not compete for the binding of HDL, in contrast to very low density lipoprotein (VLDL). It is suggested that VLDL competition is exerted by the presence of apo Cs. Degradation of HDL was relatively low and in some cases not detectable. In cases where degradation was found, inhibitors of the lysosomal pathway of protein degradation had no effect, while LDL degradation was inhibited more than 80%. In the presence of 10 fiM of monensin, the cell-association of HDL was unaffected, but the degradation was inhibited by 30%. Under similar conditions, LDL association was inhibited by 40% and LDL degradation, by 90%. Incubation of human hepatocytes with fluorescently labeled HDL (Dil-HDL) revealed (in contrast to Dil-LDL) mainly strong membranebound fluorescence and hardly any labeling of small intracellular vesicles. It is concluded that human hepatocytes possess a specific high affinity site for human HDL with recognition properties similar to those described earlier on rat hepatocytes. No evidence that the binding of HDL is actively coupled to uptake and lysosomal degradation could be obtained, indicating that binding of LDL and HDL to human hepatocytes is coupled differently to intracellular pathways.

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“…Hepatocytes accumulated cholate and taurocholate from the recirculating plasma and were able to conjugate a substantial amount of cholic acid. Shortterm cultured rat hepatocyte couplets have been shown to secrete canalicular bile in vitro [29] and cultured porcine hepatocytes were shown to accumulate bile acids more efficiently and for a longer period of time than rat or human cultured hepatocytes [30]. We choose to expose hepatocytes to a high concentration of bile acids, since in six consecutive FHF patients previously studied, we found a mean total bile acid level of 91.5 Ϯ 45.0 M [11].…”

Section: Discussionmentioning

confidence: 97%

In VitroMorphological and Functional Characterization of Isolated Porcine Hepatocytes for Extracorporeal Liver Support: Bile Acid Uptake and Conjugation

Morsiani

Pazzi

Moscioni

et al. 1998

Journal of Surgical Research

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Comparison of taurocholate accumulation in cultured hepatocytes of pig, rat and man

Cited by 25 publications

References 23 publications

Feedback Regulation of Hepatic 7α-Hydroxylase Expression by Bile Salts in the Hamster

Feedback Regulation of Hepatic 7α-Hydroxylase Expression by Bile Salts in the Hamster

Characterization in vitro of interaction of human apolipoprotein E-free high density lipoprotein with human hepatocytes.

In VitroMorphological and Functional Characterization of Isolated Porcine Hepatocytes for Extracorporeal Liver Support: Bile Acid Uptake and Conjugation

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