Differential regulation of bile acid homeostasis by the farnesoid X receptor in liver and intestine

Kim, Insook; Ahn, Sung‐Hoon; Inagaki, Takeshi; Choi, Mihwa; Ito, Shinji; Guo, Grace L.; Kliewer, Steven A.; Gonzalez, Frank J.

doi:10.1194/jlr.m700330-jlr200

Cited by 492 publications

(466 citation statements)

References 41 publications

Supporting

Mentioning

430

Contrasting

Unclassified

Order By: Relevance

“…7,8 Studies in mice with intestine-specific or liver-specific disruption of the Fxr gene revealed that administration of a synthetic FXR agonist failed to repress Cyp7a1 in animals deficient in intestinal Fxr. 9 This study thus implied an important role for intestinal Fgf15 in regulation of bile salt synthesis. …”

mentioning

confidence: 95%

High expression of the bile salt-homeostatic hormone fibroblast growth factor 19 in the liver of patients with extrahepatic cholestasis

Schaap¹,

et al. 2008

View full text Add to dashboard Cite

Fibroblast growth factor 19 (FGF19) is an endocrine factor produced by the small intestine in response to uptake of luminal bile salts. In the liver, FGF19 binds to FGF receptor-4, resulting in down-regulation of cytochrome P (CYP) 7A1 and reduced bile salt synthesis. Down-regulation of CYP7A1 under cholestatic conditions has been attributed to bile salt-mediated induction of the transcriptional repressor short heterodimer partner (SHP), because the interrupted enterohepatic cycle of bile salts is thought to abrogate intestinal FGF19 production and thus result in lowering of plasma FGF19 levels. Unexpectedly, we observed marked elevation of plasma FGF19 in patients with extrahepatic cholestasis caused by a pancreatic tumor (2.3 ؎ 2.3 in cholestatic versus 0.40 ؎ 0.25 ng/mL and 0.29 ؎ 0.12 ng/mL in postcholestatic patients who received preoperative drainage by biliary stenting, P ‫؍‬ 0.004, and noncholestatic control patients, P ‫؍‬ 0.04, respectively). Although FGF19 messenger RNA (mRNA) is virtually absent in normal liver, FGF19 mRNA was strongly increased (31-fold to 374-fold, P < 0.001) in the liver of cholestatic patients in comparison with drained and control patients. In the absence of changes in SHP mRNA, CYP7A1 mRNA was strongly reduced (7.2-fold to 24-fold, P < 0. B ecause they are potent detergents, synthesis of bile salts is subject to rigorous regulation. 1,2 The principal target for control of bile salt synthesis is the cytochrome P (CYP) 7A1 gene, which encodes the ratedetermining enzyme in the dominant biosynthetic pathway. Regulation of CYP7A1 occurs primarily at the transcriptional level and involves several nuclear hormone receptors. Among these ligand-activated transcription factors, the bile salt receptor FXR (farnesoid-X receptor) plays a key role in bile salt-mediated repression of CYP7A1. 2-4 Activation of hepatic FXR induces expression of short heterodimer partner (SHP), a transcriptional repressor that diminishes the transactivation potential of several transcription factors required for efficient CYP7A1 expression. [3][4][5] Activation of intestinal FXR by reabsorbed bile salts induces expression and portal release of FGF19 (fibroblast growth factor 19, termed Fgf15 in rodents). 6,7 Binding of FGF19/ Fgf15 to the cell surface receptor FGFR4 results in activation of mitogen-activated protein kinase pathways and downregulation of CYP7A1. 7,8 Studies in mice with intestine-specific or liver-specific disruption of the Fxr gene revealed that administration of a synthetic FXR agonist failed to repress Cyp7a1 in animals deficient in intestinal Fxr. 9 This study thus implied an important role for intestinal Fgf15 in regulation of bile salt synthesis.

show abstract

mentioning

confidence: 95%

High expression of the bile salt-homeostatic hormone fibroblast growth factor 19 in the liver of patients with extrahepatic cholestasis

Schaap¹,

et al. 2008

View full text Add to dashboard Cite

show abstract

“…Bile acids have been proven to significantly contribute to the regulation of whole-body metabolism through the stimulation of TGR5 receptors (Kim et al 2007, Penney et al 2015, Vitek & Haluzik 2016. Bile acid sequestrants are a treatment option for patients with T2DM, which is approved in the USA (Hansen et al 2014).…”

Section: :1mentioning

confidence: 99%

Endocrine effects of duodenal–jejunal exclusion in obese patients with type 2 diabetes mellitus

Kaválková

Mráz

Trachta

et al. 2016

Journal of Endocrinology

View full text Add to dashboard Cite

Duodenal-jejunal bypass liner (DJBL) is an endoscopically implantable device designed to noninvasively mimic the effects of gastrointestinal bypass operations by excluding the duodenum and proximal jejunum from the contact with ingested food. The aim of our study was to assess the influence of DJBL on anthropometric parameters, glucose regulation, metabolic and hormonal profile in obese patients with type 2 diabetes mellitus (T2DM) and to characterize both the magnitude and the possible mechanisms of its effect. Thirty obese patients with poorly controlled T2DM underwent the implantation of DJBL and were assessed before and 1, 6 and 10 months after the implantation, and 3 months after the removal of DJBL. The implantation decreased body weight, and improved lipid levels and glucose regulation along with reduced glycemic variability. Serum concentrations of fibroblast growth factor 19 (FGF19) and bile acids markedly increased together with a tendency to restoration of postprandial peak of GLP1. White blood cell count slightly increased and red blood cell count decreased throughout the DJBL implantation period along with decreased ferritin, iron and vitamin B12 concentrations. Blood count returned to baseline values 3 months after DJBL removal. Decreased body weight and improved glucose control persisted with only slight deterioration 3 months after DJBL removal while the effect on lipids was lost. We conclude that the implantation of DJBL induced a sustained reduction in body weight and improvement in regulation of lipid and glucose. The increase in FGF19 and bile acids levels could be at least partially responsible for these effects.

show abstract

“…This story emerges from the paradoxical observation that although feeding animals diets enriched in bile acids suppresses their own production by decreasing CYP7A1 expression, adding bile acids to the medium of isolated hepatocytes has no effect (7). FXR is essential for bile acid feedback regulation through the suppression of Cyp7a1 expression, but quite surprisingly, it is intestinal FXR, not hepatic FXR, that mediates the tuning of this pathway (8). The abilities of individual bile acids to activate FXR (9, 10) correlate with their detergent properties (2).…”

mentioning

confidence: 99%

“…Uptake of bile acids that activate FXR by the ileal enterocyte induces the expression of fibroblast growth factor is (FGF15) (11)(12)(13). FGF15 is released into the portal circulation and then binds to the hepatocyte basolateral receptor FGFR4, leading to the repression of Cyp7A1 expression (8,(12)(13)(14)(15). In short, FGF15 is the link between FXR sensing of bile acids in enterocytes and expression of Cyp7A1 in hepatocytes.…”

mentioning

confidence: 99%

Deletion of the ileal basolateral bile acid transporter identifies the cellular sentinels that regulate the bile acid pool

Davis

Attie

2008

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

View full text Add to dashboard Cite

Differential regulation of bile acid homeostasis by the farnesoid X receptor in liver and intestine

Cited by 492 publications

References 41 publications

High expression of the bile salt-homeostatic hormone fibroblast growth factor 19 in the liver of patients with extrahepatic cholestasis

High expression of the bile salt-homeostatic hormone fibroblast growth factor 19 in the liver of patients with extrahepatic cholestasis

Endocrine effects of duodenal–jejunal exclusion in obese patients with type 2 diabetes mellitus

Deletion of the ileal basolateral bile acid transporter identifies the cellular sentinels that regulate the bile acid pool

Contact Info

Product

Resources

About