Regulation of bile acid synthesis in humans: Effect of treatment with bile acids, cholestyramine or simvastatin on cholesterol 7α-hydroxylation ratesin vivo

Bertolotti, Marco; Abate, N.; Loria, Paola; Dilengite, Michele A.; Carubbi, Francesca; Pinetti, Adriano; Digrisolo, Antonia; Carulli, Nicola

doi:10.1002/hep.1840140515

Cited by 61 publications

(51 citation statements)

References 46 publications

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“…These results are also in agreement with the absence of hypercholesterolemic activity of chenodeoxycholic acid in treated patients [97][98][99][100][101][102] and animals (data not shown). These results illuminate the fact that the simplistic idea proposing that FXR antagonists should lead to the discovery of new hypocholesterolemic drugs must take into account the multiple regulatory loops controlling the metabolism of cholesterol in vivo.…”

Section: Regulation Of Cholesterol 7α-hydroxylase By 11-bisphosphonasupporting

confidence: 94%

“…These results might also be explained by an increased hepatic uptake of plasma cholesterol by the induction of LDL receptors demonstrated in vitro by Taniguchi et al [99] for chenodeoxycholic and deoxycholic acid. Bertolotti et al [98] also made the observation that ursodeoxycholic acid, the 7β epimer of chenodeoxycholic acid which does not activate FXR, did not affect the activity of 7α-hydroxylase in man. Ursodeoxycholic acid did not affect LDL cholesterol level in patients with primary hypercholesterolemia [100].…”

Section: Other Pathways Affecting Cholesterol 7α-hydroxylase Activitymentioning

confidence: 91%

“…As observed in the animal model ursodeoxycholic acid did not affect cholesterol 7α-hydroxylase activity. Bertolotti et al [98] observed in patients (mainly hyperlipidemic) receiving chenodeoxycholic or deoxycholic acid for 4 to 6 weeks a suppression of cholesterol 7α-hydroxylase of 47% and 78% respectively. These authors observed a decrease in plasma total and LDL cholesterol in deoxycholic acid treated patients.…”

Section: Lxr Agonistsmentioning

confidence: 97%

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The Nuclear Receptors FXR and LX alpha Potential Targets for the Development of Drugs Affecting Lipid Metabolism and Neoplastic Diseases

Niesor¹,

Flach²,

Lopes-Antoni³

et al. 2001

CPD

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The orphan nuclear receptors FXR and LXRalpha have become challenging targets for the discovery of new therapeutic agents. Bile acids and hydroxysterol intermediates are the respective natural ligands of these two structurally and functionally closely related receptors. Both FXR and LXRalpha; are thought to play a major role in the control of cholesterol catabolism by regulating the expression of cholesterol 7alpha-hydroxylase, the rate limiting enzyme of bile acid synthesis. Reverse cholesterol transport might also be affected by FXR and LXR since they control the expression of PLTP and CETP, two proteins involved in the transfer of phospholipid, cholesterol and cholesteryl esters among plasma lipoproteins. A new class of potent synthetic activators of FXR, the 1,1-bisphosphonate esters, has been discovered which up regulate the Intestinal Bile Acid Binding Protein gene (I-BABP) as demonstrated for chenodeoxycholic acid, however there are no known synthetic activators yet identified for LXRalpha. The evaluation of FXR as a potential target for the development of drugs affecting plasma cholesterol can take advantage of the fact that the activators of FXR (farnesol, bile acids and the 1,1-bisphosphonate esters) have been studied in various in vitro and in vivo models. Administration of chenodeoxycholic acid to animals and man did not result in the increase in plasma cholesterol expected from a decrease in cholesterol 7alpha-hydroxylase expression. Like farnesol, the 1,1-bisphosphonate esters increase the rate of degradation of HMGCoA reductase and have the unexpected property of inducing hypocholesterolemia in normal animals. The natural and synthetic FXR agonists trigger differentiation, inhibit cell proliferation and are potent inducers of apoptosis. The 1,1-bisphosphonate ester SR-45023A (Apomine) is presently being developed as an antineoplastic drug.

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Section: Regulation Of Cholesterol 7α-hydroxylase By 11-bisphosphonasupporting

confidence: 94%

Section: Other Pathways Affecting Cholesterol 7α-hydroxylase Activitymentioning

confidence: 91%

Section: Lxr Agonistsmentioning

confidence: 97%

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The Nuclear Receptors FXR and LX alpha Potential Targets for the Development of Drugs Affecting Lipid Metabolism and Neoplastic Diseases

Niesor¹,

Flach²,

Lopes-Antoni³

et al. 2001

CPD

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“…Interestingly, FXR Ϫ/Ϫ knockout mice (5) display a proatherogenic lipid profile, having increased circulating total cholesterol, triglycerides, phospholipids, and cholesterol esters, decreased hepatic scavenger receptor B1, and an increase in apolipoprotein B1. Although bile acid sequestrants are used to treat hypercholesterolemia, bile acids such as chenodeoxycholic acid (CDCA) lower circulating cholesterol in some patients (6).…”

mentioning

confidence: 99%

Expression and activation of the farnesoid X receptor in the vasculature

Bishop‐Bailey

Walsh

Warner

2004

Proc. Natl. Acad. Sci. U.S.A.

207

153

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The farnesoid X receptor͞bile acid receptor (FXR) is a recently discovered member of the nuclear hormone superfamily. FXR ligands have been proposed as targets in cardiovascular disease, regulating cholesterol metabolism and bile acid transport and metabolism in the liver and gastrointestinal tract. When we used a human cardiovascular tissue array, we found that FXR is expressed in a variety of normal and pathological human tissue. Particularly high levels of FXR were found in the vasculature and in a number of different metastatic cancers, as well as the previously identified target tissues of the liver, small intestine, and kidney. In vitro, FXR is present in rat and human vascular smooth muscle cells. When treated with a range of FXR ligands, vascular smooth muscle cells undergo apoptosis in a manner that correlates with the ligands' ability to activate FXR. Furthermore, FXR activators induce mRNA for the FXR target genes, phospholipid transfer protein, and the small heterodimer partner. FXR therefore is a functional protein in the vasculature that may provide a direct target for the treatment of proliferative and dyslipidaemic diseases.

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“…10 In general, with increasing hydrophobicity, bile acids gain a higher capacity to suppress bile acid synthesis 13 in cultured hepatoma cells, [14][15][16] experimental animals, 10,13,17,18 and humans. 19,20 Therefore, an increased intestinal formation of secondary bile acids during expansion of the primary bile acid pool could result in a decreased hepatic formation of primary bile acids. In addition, the availability of newly synthesized cholesterol as substrate for bile acid formation may be a further rate-limiting factor of bile acid synthesis in rats [21][22][23][24] and humans.…”

mentioning

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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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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Regulation of bile acid synthesis in humans: Effect of treatment with bile acids, cholestyramine or simvastatin on cholesterol 7α-hydroxylation ratesin vivo

Cited by 61 publications

References 46 publications

The Nuclear Receptors FXR and LX alpha Potential Targets for the Development of Drugs Affecting Lipid Metabolism and Neoplastic Diseases

The Nuclear Receptors FXR and LX alpha Potential Targets for the Development of Drugs Affecting Lipid Metabolism and Neoplastic Diseases

Expression and activation of the farnesoid X receptor in the vasculature

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

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