Transcriptional regulation of hepatic sterol 27-hydroxylase by bile acids

Vlahčevič, Z. Reno; Jairath, S. K.; Heuman, D. M.; Stravitz, R. Todd; Hylemon, Phillip B.; Avadhani, Narayan G.; Pandak, W. M.

doi:10.1152/ajpgi.1996.270.4.g646

Cited by 38 publications

(43 citation statements)

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“…However, it is impossible to exclude that it was the high dose of cholate alone that regulated synthesis of both primary bile acids in hamsters. Infusion experiments in rats 10 coordinate down-regulation of cholesterol 7␣-and 27-hydroxylase [36][37][38] has been proposed for the rat, although this has not been confirmed consistently, 35 and species differences may also influence the results. 39 With respect to long-term effects on synthesis from de novo cholesterol, the infusion of conjugated cholate in a low dose and of deoxycholate in a high dose increased the amount of cholate synthesis from de novo cholesterol, most likely mediated by its increased availability, whereas de novo proportions of chenodeoxycholate remained unchanged.…”

Section: Discussionmentioning

confidence: 99%

“…Bile acid synthesis via 27-hydroxylase (acidic pathway) accounts for a substantial fraction of bile acid synthesis under physiological conditions and after long-term bile drainage, at least in the rat 32,33 and mouse. 34 Additionally, modulation of this alternative pathway may differ from that of the classical cholesterol 7␣-hydroxylation pathway 35 or between species like rats [36][37][38] and rabbits. 39 Therefore, direct quantitation of synthesized end-products is necessary to include all molecular mechanisms relevant for regulation of bile acid synthesis.…”

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confidence: 99%

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Complex feedback regulation of bile acid synthesis in the hamster: The role of newly synthesized cholesterol

et al. 1999

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Hepatic bile acid synthesis is regulated by recirculating bile acids, possibly by modulating the availability of newly synthesized and preformed cholesterol. Because data in the hamster on this mechanism are lacking, we fitted these animals with an extracorporeal bile duct and administered tritiated water intraperitoneally to label newly formed cholesterol. After interruption of the enterohepatic circulation, physiological and double-physiological doses of conjugated cholate (25 or 50 mol/100 g · h) or of unconjugated deoxycholate (6 or 12 mol) were infused intraduodenally for 54 hours and compared with controls. De novo and preformed cholesterol directly secreted into bile or used for cholate and chenodeoxycholate synthesis were quantitated by high-pressure liquid chromatography (HPLC)-liquid scintillation. Directly after depletion of the bile acid pool (6-9 hours) at nearly physiological conditions, chenodeoxycholate synthesis was significantly reduced by cholate and deoxycholate by up to 45% to 51%, whereas cholate formation decreased by Ϸ22% during deoxycholate. This short-term effect was mainly mediated by reduced synthesis from preformed cholesterol. After long-term bile depletion (30-54 hours), bile acid synthesis returned to control levels during 25 mol of cholate and of both deoxycholate doses. In contrast, only 50 mol of cholate prevented derepression of bile acid synthesis. This long-term effect was mainly attributed to a diminished formation from de novo cholesterol exceeding the reduced synthesis from preformed cholesterol. In summary, short-and long-term regulation of bile acid synthesis in hamsters differs with respect to availabilities of preformed and de novo cholesterol. (HEPATOL-OGY 1999;30:230-237.)

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Complex feedback regulation of bile acid synthesis in the hamster: The role of newly synthesized cholesterol

et al. 1999

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“…4,[32][33][34] In vivo, however, multiple cell types are present in the liver, and it is possible that nonparenchymal sinusoidal cells may play a role in mediating cholestatic insults to hepatocytes. 35 In preliminary experiments using transfected primary rat hepatocytes, Karpen et al showed that levels of bile salts similar to those used in the current study suppressed the activity of the rat ntcp promoter.…”

Section: Discussionmentioning

confidence: 99%

Enhanced Na+-dependent bile salt uptake by WIF-B cells, a rat hepatoma hybrid cell line, following growth in the presence of a physiological bile salt

et al. 1998

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Western blots immunostained for the basolateral Na ؉ -dependent plasma membrane protein, ntcp, revealed the appropriate Ϸ50-kd band in control and TC-grown cells, and confocal immunofluorescence microscopy demonstrated staining along the basolateral plasma membrane. Northern blots hybridized with a cDNA probe directed against ntcp indicated a modest TC-induced increase in mRNA levels. Reverse-transcriptase polymerase chain reaction (RT-PCR) using RNA isolated from WIF-B cells and oligonucleotide primers specific for rat ntcp or human NTCP transcripts revealed only the presence of the rat ntcp transcript. We conclude that bile salts, at concentrations normally found in mammalian portal blood, may be capable of promoting enhanced hepatocellular bile salt uptake via an increase in basolateral Na ؉ -dependent plasma membrane transport capacity. (HEPATOLOGY 1998;27:191-199.)The mammalian liver is continually exposed to low concentrations of bile salts present in portal and peripheral blood. Hepatocytes avidly take up bile salts across the basolateral plasma membrane and rapidly secrete them into bile; less than 5% of secreted bile salts are derived from de novo synthesis within the hepatocyte. 1 In rats, the postprandial bile salt concentration in the portal blood is Ϸ60 µmol/L, with taurocholate (TC) comprising up to half of the bile salt species. 2 In humans, the bile salt load reaching the liver fluctuates considerably over a 24-hour period, with portal vein plasma concentrations ranging from Ϸ14 µmol/L in the fasting state to Ϸ43 µmol/L in the postprandial state. 3 Hepatocytes are thus exposed routinely to changes in rates of bile salt delivery, and therefore must respond with variable rates of bile salt uptake across the basolateral plasma membrane. High plasma bile salt concentrations (up to 1 mmol/L) are associated with down-regulation of basolateral bile salt uptake into hepatocytes. 4 It is unclear, however, whether plasma bile salt concentrations within physiological ranges may promote bile salt uptake into hepatocytes.Difficulties are encountered when examining the physiological role of bile salts in intact animals, because many variables change simultaneously when conducting in vivo studies. A major experimental problem also is encountered when addressing normal bile salt regulation of hepatic physiology in vitro, because of the difficulty in maintaining liver preparations with stable rates of basolateral bile salt uptake. Isolated perfused rat livers maintain physiological rates of bile salt uptake and secretion for up to 3 hours, but bile flow decreases thereafter. 5 Isolated rat hepatocytes exhibit profound decreases in rates of bile salt uptake over the first 72 hours of primary culture. [6][7][8] Bile salt transport may be virtually absent in cultured hepatocyte tumor cell lines. 9 Recently, an in vitro polarized hepatocyte cell system, WIF-B cells, has been reported by Hubbard et al. 10,11 as a refinement of an existing rat hepatoma-human fibroblast cell line developed by Cassio et al. 12 WIF-B cell...

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“…The "acidic" pathway of bile acid biosynthesis is initiated by the mitochondrial enzyme, sterol 27-hydroxylase (CYP27A1) (1). Oxysterol intermediates of the "acidic" pathway such as 27-hydroxycholesterol and 25-hydroxycholesterol have been shown to be regulators of cholesterol homeostasis (2)(3)(4)(5)(6)(7)(8).…”

Section: Introductionmentioning

confidence: 99%

Sulfated oxysterol, 25HC3S, is a potent regulator of lipid metabolism in human hepatocytes

Ren

Rodríguez‐Agudo

et al. 2007

Biochemical and Biophysical Research Communications

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Recently, a novel oxysterol, 5-cholesten-3β, 25-diol 3-sulfate (25HC3S) was identified in primary rat hepatocytes following overexpression of the cholesterol transport protein, StarD1. This oxysterol was also detected in human liver nuclei. In the present study, 25HC3S was chemically synthesized. Addition of 25HC3S (6 μM) to human hepatocytes markedly inhibited cholesterol biosynthesis. Quantitative RT-PCR and Western blot analysis showed that 25HC3S strongly decreased HMG-CoA reductase mRNA and protein levels. Coincidently, 25HC3S inhibited the activation of sterol regulatory element binding proteins (SREBPs), suggesting that inhibition of cholesterol biosynthesis occurred via blocking SREBP-1 activation, and subsequently inhibiting the expression of HMG CoA reductase. 25HC3S decreased SREBP-1 mRNA levels and inhibited the expression of target genes encoding acetyl CoA carboxylase-1 (ACC-1) and fatty acid synthase (FAS). In contract, 25-hydroxycholesterol increased SREBP1 and FAS mRNA levels in primary human hepatocytes. The results imply that 25HC3S is a potent regulator of SREBPs mediated lipid metabolism.

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Transcriptional regulation of hepatic sterol 27-hydroxylase by bile acids

Cited by 38 publications

References 0 publications

Complex feedback regulation of bile acid synthesis in the hamster: The role of newly synthesized cholesterol

Complex feedback regulation of bile acid synthesis in the hamster: The role of newly synthesized cholesterol

Enhanced Na+-dependent bile salt uptake by WIF-B cells, a rat hepatoma hybrid cell line, following growth in the presence of a physiological bile salt

Sulfated oxysterol, 25HC3S, is a potent regulator of lipid metabolism in human hepatocytes

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