Identification of a hormonal basis for gallbladder filling

Choi, Mihwa; Moschetta, Antonio; Bookout, Angie L.; Li, Peng; Umetani, Michihisa; Holmstrom, Sam R.; Suino-Powell, Kelly; Xu, H. Eric; Richardson, James A.; Gerard, Robert D.; Mangelsdorf, David J.; Kliewer, Steven A.

doi:10.1038/nm1501

Cited by 259 publications

(205 citation statements)

References 15 publications

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“…As the bile acids transit the intestine, they increase production of FGF15 from the distal intestine to regulate bile acid production in the liver. Additionally, intestinal FGF15 stimulates gall bladder filling with bile, which is enhanced during fasting (70). Interestingly, the fasting-dependent increase in intestinal FGF15 mRNA in our experiments (Fig.…”

Section: Discussionsupporting

confidence: 53%

“…9, right). The mouse gallbladder expresses only minor amounts of FGFR4 but relatively higher levels of FGFR3, which is also a target for FGF15 signaling and probably functions to relay the FGF15 signal for gallbladder filling (70). It is likely that induction of hepatic CYP7A1 at a time when gall bladder filling is stimulated is important to provide the correct balance of bile acids to mix with available cholesterol and phospholipids for optimal bile consistency.…”

Section: Discussionmentioning

confidence: 99%

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FGF15/FGFR4 Integrates Growth Factor Signaling with Hepatic Bile Acid Metabolism and Insulin Action

Shin

Osborne

2009

Journal of Biological Chemistry

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The current studies show FGF15 signaling decreases hepatic forkhead transcription factor 1 (FoxO1) activity through phosphatidylinositol (PI) 3-kinase-dependent phosphorylation. The bile acid receptor FXR (farnesoid X receptor) activates expression of fibroblast growth factor (FGF) 15 in the intestine, which acts through hepatic FGFR4 to suppress cholesterol-7␣ hydroxylase (CYP7A1) and limit bile acid production. Because FoxO1 activity and CYP7A1 gene expression are both increased by fasting, we hypothesized CYP7A1 might be a FoxO1 target gene. Consistent with recently reported results, we show CYP7A1 is a direct target of FoxO1. Additionally, we show that the PI 3-kinase pathway is key for both the induction of CYP7A1 by fasting and the suppression by FGF15. FGFR4 is the major hepatic FGF receptor isoform and is responsible for the hepatic effects of FGF15. We also show that expression of FGFR4 in liver was decreased by fasting, increased by insulin, and reduced by streptozotocin-induced diabetes, implicating FGFR4 as a primary target of insulin regulation. Because insulin and FGF both target the PI 3-kinase pathway, these observations suggest FoxO1 is a key node in the convergence of FGF and insulin signaling pathways and functions as a key integrator for the regulation of glucose and bile acid metabolism.Hepatic cholesterol is converted to bile acids, secreted into the gallbladder, and during a meal is released into the small intestine to enhance digestion and absorption of dietary lipids and fat-soluble vitamins. The majority of the bile acid pool (95%) is recycled back to the liver, whereas the remaining 5% is eliminated through fecal excretion (1, 2). This is an important route for the elimination of excess cholesterol and underscores the importance that bile acids play in regulating mammalian cholesterol metabolism. The initial and rate-controlling step in the classic pathway for cholesterol conversion into bile acids is catalyzed by cholesterol 7␣-hydroxylase (CYP7A1).2 CYP7A1 regulation is primarily transcriptional, and expression of its gene is dynamically regulated by hormones and metabolites (2-6). Importantly, bile acids themselves regulate CYP7A1 gene expression through a multicomponent negative feedback pathway. One of the molecular pathways for bile acid regulation is initiated by the activation of the farnesoid X receptor (FXR) responding directly to bile acid agonists (7). Ligand-activated FXR directly binds to a site in the promoter for the small heterodimer partner (SHP) gene and induces expression of SHP mRNA (8, 9). The translated SHP protein lacks the signature nuclear receptor zinc finger DNA binding domain but uses its conserved dimerization motif to form protein-protein contacts with DNA bound activators, usually other nuclear receptors, to inhibit or interfere with their activation potential (10, 11).The first identified target for SHP repression was the CYP7A1 promoter, and SHP was proposed to interfere with activation by the DNA-bound monomeric liver receptor homologue 1 (LRH-1) nucl...

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Section: Discussionsupporting

confidence: 53%

Section: Discussionmentioning

confidence: 99%

FGF15/FGFR4 Integrates Growth Factor Signaling with Hepatic Bile Acid Metabolism and Insulin Action

Shin

Osborne

2009

Journal of Biological Chemistry

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“…Bile flows of overnight fasted WT and Shp Ϫ/Ϫ mice were measured as previously described 15 with slight modification. Briefly, fasted mice were anesthetized by intraperitoneal injection of avertin.…”

Section: Methodsmentioning

confidence: 99%

Loss of orphan receptor small heterodimer partner sensitizes mice to liver injury from obstructive cholestasis

et al. 2008

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The orphan nuclear hormone receptor small heterodimer partner (SHP) regulates the expression of several genes involved in bile acid homeostasis in the liver. Because bile acid toxicity is a major source of liver injury in cholestatic disease, we explored the role of SHP in liver damage induced by common bile duct ligation (BDL). Shp ؊/؊ mice show increased sensitivity in this model of acute obstructive cholestasis, with greater numbers of bile infarcts and higher mortality than wild-type C57BL/6 mice. This increased sensitivity could not be accounted for by differences in expression of bile acid homeostatic genes 2 or 5 days after BDL. Instead, higher basal expression of such genes, including the key biosynthetic enzyme cholesterol 7␣ hydroxylase (Cyp7A1) and the bile salt export pump, is associated with both an increase in bile flow prior to BDL and an increase in acute liver damage at only 1.5 hours after BDL in Shp ؊/؊ mice, as shown by bile infarcts. At 3 hours, Cyp7A1 expression still remained elevated in Shp ؊/؊ with respect to wild-type mice, and the hepatic and serum bile acid levels and total hepatobiliary bile acid pool were significantly increased. The increased sensitivity of mice lacking SHP contrasts with the decreased sensitivity of mice lacking the farnesoid X receptor (FXR; nuclear receptor subfamily 1, group H, member 4) to BDL, which has been associated with decreased intraductal pressure and fewer bile infarcts. Conclusion: We propose that differences in acute responses to BDL, particularly the early formation of bile infarcts, are a primary determinant of the differences in longer term sensitivity of the Fxr ؊/؊ and Shp ؊/؊ mice to acute obstructive cholestasis. (HEPATOLOGY 2008;

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“…The secreted FGF15 signals from the intestine to the liver to repress CYP7A1 expression through a FGF receptor 4 (FGFR4)-mediated mechanism (6). In addition, the FGF15/FGF19 feedback loop prevents bile excretion into the digestive tract by promoting gallbladder filling (7).…”

mentioning

confidence: 99%

“…The role of FGF15/FGF19 in bile acid homeostasis is supported by the increased liver CYP7A1 expression and decreased gallbladder volume that occurs in FGF15-deficient mice (FGF15 Ϫ/Ϫ mice) and in FGFR4-deficient mice (FGFR4 Ϫ/Ϫ mice) (6,7). FGF19 is mainly expressed in the gall bladder and the small intestine but is also found in circulation (8,9).…”

mentioning

confidence: 99%

Liver-specific Activities of FGF19 Require Klotho beta

Lin

Wang

Blackmore

et al. 2007

Journal of Biological Chemistry

251

230

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Hepatocyte function is regulated by members of the fibroblast growth factor (FGF) family of proteins, but little is known about the specific molecular mechanisms of this endocrine pathway. FGF19 regulates bile acid homeostasis and gall bladder filling; FGF19 binds only to FGF receptor 4 (FGFR4), but its liver-specific activity cannot be explained solely by the distribution of this receptor. Although it has been suggested that Klotho beta (KLB) may have a role in mediating FGF19 activity, we have provided for the first time definitive evidence that KLB is required for FGF19 binding to FGFR4, intracellular signaling, and downstream modulation of gene expression. We have shown that FGFR4 is widely distributed in mouse, whereas KLB distribution is more restricted. Liver was the only organ in which both genes were abundantly expressed. We show that in mice, FGF19 injection triggers liver-specific induction of c-Fos and repression of CYP7A1. The tissue-specific activity of FGF19 supports the unique intersection of KLB and FGFR4 distribution in liver. These studies define KLB as a novel FGFR4 coreceptor required for FGF19 liver specific functions.Bile acids are amphipathic cholesterol metabolites essential for the absorption of lipophilic nutrients and cholesterol homeostasis (1). They are synthesized by the liver and stored in the gall bladder (2). The cycle of gallbladder filling and emptying controls the flow of bile into the intestine for digestion. Because bile acid accumulation can lead to hepatotoxicity and cholestasis, this process is tightly regulated (3) by a negative feedback mechanism. Bile acids bind to the farnesoid X receptor, a member of the nuclear receptor family of ligand-regulated transcription factors, which is highly expressed in liver and intestine. In the liver, farnesoid X receptor activation represses the transcription of cholesterol 7␣-hydroxylase (CYP7A1), 2 a rate-limiting enzyme in the biosynthesis of bile acids (4, 5). In the small intestine, bile acid activation of farnesoid X receptor induces the expression of fibroblast growth factor 15 (FGF15; mouse orthologue of human FGF19). The secreted FGF15 signals from the intestine to the liver to repress CYP7A1 expression through a FGF receptor 4 (FGFR4)-mediated mechanism (6). In addition, the FGF15/FGF19 feedback loop prevents bile excretion into the digestive tract by promoting gallbladder filling (7).The role of FGF15/FGF19 in bile acid homeostasis is supported by the increased liver CYP7A1 expression and decreased gallbladder volume that occurs in FGF15-deficient mice (FGF15 Ϫ/Ϫ mice) and in FGFR4-deficient mice (FGFR4

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Identification of a hormonal basis for gallbladder filling

Cited by 259 publications

References 15 publications

FGF15/FGFR4 Integrates Growth Factor Signaling with Hepatic Bile Acid Metabolism and Insulin Action

FGF15/FGFR4 Integrates Growth Factor Signaling with Hepatic Bile Acid Metabolism and Insulin Action

Loss of orphan receptor small heterodimer partner sensitizes mice to liver injury from obstructive cholestasis

Liver-specific Activities of FGF19 Require Klotho beta

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