The Role of FGF19 and MALRD1 in Enterohepatic Bile Acid Signaling
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ABSTRACT:
SUBMITTER: Wang L
PROVIDER: S-EPMC8804323 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BACKGROUND AND PURPOSE:Ursodeoxycholic acid (UDCA) is the first-line treatment for primary biliary cholangitis, but its effects on the enterohepatic circulation of bile acid (BA) have been under-investigated. Therefore, we studied the influence of UDCA on BA enterohepatic circulation in vivo and the mechanisms by which UDCA affects the BA kinetics. EXPERIMENTAL APPROACH:Mice were treated with UDCA and other BAs to observe changes in BA pool and BA transporters involved in enterohepatic circulation. Isotope dilution techniques and biochemical analyses were applied to study BA kinetics after oral administration of UDCA, and the mechanism involved. KEY RESULTS:Oral administration of UDCA in mice reduced the overall BA pool and produced a unique BA profile with high-abundance conjugated UDCA species, including tauroursodeoxycholic acid (TUDCA) and GUDCA. We found increased expression of several main BA transporters in the ileum and liver. BA kinetic experiment showed that feeding UDCA shortened cycling time of BA and accelerated BA enterohepatic circulation. Additionally, we found evidence that the effect of UDCA administration on accelerating BA enterohepatic circulation was due to the inhibition of farnesoid X receptor (FXR) signalling in the ileum and FGF15/19 in the liver. CONCLUSION AND IMPLICATIONS:Oral administration of UDCA produced a unique BA profile with high-abundance TUDCA and GUDCA and significantly accelerated BA enterohepatic circulation through the inhibition of intestinal FXR signalling and reduced level of FGF15/19, which in turn, induced the expression of BA transporters in the liver. These findings highlight a critical role for UDCA in maintaining the homeostasis of BA enterohepatic circulation in vivo.
| S-EPMC6637225 | biostudies-literature
Project description:We identified a mutation in the Diet1 gene in a mouse strain that is resistant to hyperlipidemia and atherosclerosis. Diet1 encodes a 236 kD protein consisting of tandem low-density lipoprotein receptor and MAM (meprin-A5-protein tyrosine phosphatase mu) domains and is expressed in the enterocytes of the small intestine. Diet1-deficient mice exhibited an elevated bile acid pool size and impaired feedback regulation of hepatic Cyp7a1, which encodes the rate-limiting enzyme in bile acid synthesis. In mouse intestine and in cultured human intestinal cells, Diet1 expression levels influenced the production of fibroblast growth factor 15/19 (FGF15/19), a hormone that signals from the intestine to liver to regulate Cyp7a1. Transgenic expression of Diet1, or adenoviral-mediated Fgf15 expression, restored normal Cyp7a1 regulation in Diet-1-deficient mice. Diet1 and FGF19 proteins exhibited overlapping subcellular localization in cultured intestinal cells. These results establish Diet1 as a control point in enterohepatic bile acid signaling and lipid homeostasis.
| S-EPMC3956443 | biostudies-literature
Project description:Background and aimsBile acid malabsorption (BAM) is a debilitating disease characterized by loose stools and high stool frequency. The pathophysiology of BAM is not well-understood. We investigated postprandial enterohepatic and gluco-metabolic physiology, as well as gut microbiome composition and fecal bile acid content in patients with BAM.MethodsTwelve participants with selenium-75 homocholic acid taurine test-verified BAM and 12 healthy controls, individually matched on sex, age, and body mass index, were included. Each participant underwent 2 mixed meal tests (with and without administration of the bile acid sequestrant colesevelam) with blood sampling and evaluation of gallbladder motility; bile acid content and microbiota composition were evaluated in fecal specimens.ResultsPatients with BAM were characterized by increased bile acid synthesis as assessed by circulating 7-alpha-hydroxy-4-cholesten-3-one, fecal bile acid content, and postprandial concentrations of glucose, insulin, C-peptide, and glucagon. The McAuley index of insulin sensitivity was lower in patients with BAM than that in healthy controls. In patients with BAM, colesevelam co-administered with the meal reduced postprandial concentrations of bile acids and fibroblast growth factor 19 and increased 7-alpha-hydroxy-4-cholesten-3-one concentrations but did not affect postprandial glucagon-like peptide 1 responses or other gluco-metabolic parameters. Patients with BAM were characterized by a gut microbiome with low relative abundance of bifidobacteria and high relative abundance of Blautia, Streptococcus, Ruminococcus gnavus, and Akkermansia muciniphila.ConclusionPatients with BAM are characterized by an overproduction of bile acids, greater fecal bile acid content, and a gluco-metabolic profile indicative of a dysmetabolic prediabetic-like state, with changes in their gut microbiome composition potentially linking their enterohepatic pathophysiology and their dysmetabolic phenotype. ClinicalTrials.gov number NCT03009916.
| S-EPMC11307667 | biostudies-literature
Project description:Farnesoid-X-Receptor (FXR) plays a central role in maintaining bile acid (BA) homeostasis by transcriptional control of numerous enterohepatic genes, including intestinal FGF19, a hormone that strongly represses hepatic BA synthesis. How activation of the FGF19 receptor at the membrane is transmitted to the nucleus for transcriptional regulation of BA levels and whether FGF19 signaling posttranslationally modulates function of FXR remain largely unknown. Here we show that FXR is phosphorylated at Y67 by non-receptor tyrosine kinase, Src, in response to postprandial FGF19, which is critical for its nuclear localization and transcriptional regulation of BA levels. Liver-specific expression of phospho-defective Y67F-FXR or Src-downregulation in mice result in impaired homeostatic responses to acute BA feeding, and exacerbate cholestatic pathologies upon drug-induced hepatobiliary insults. Also, the hepatic FGF19-Src-FXR pathway is defective in primary biliary cirrhosis patients. This study identifies Src-mediated FXR phosphorylation as a potential therapeutic target and biomarker for BA-related enterohepatic diseases.
2018-04-27 | GSE113707 | GEO
Project description:The involvement of bile salt-fibroblast growth factor 19 (FGF19) signaling in human liver regeneration (LR) is not well studied. Therefore, we studied aspects of bile salt-FGF19 signaling shortly after liver resection in patients. We compared plasma bile salt and FGF19 levels in arterial, portal and hepatic venous blood, calculated venous-arterial differences (ΔVA), and determined hepatic transcript levels on two intra-operative time points: before (< 1 hour) and immediately after (> 2-3 hours) liver resection (i.e., following surgery). Postoperative bile salt and FGF19 levels were assessed on days 1, 2, and 3. LR was studied by computed tomography (CT)-liver volumetry. Following surgery, the liver, arterial, and portal bile salt levels were elevated (P < 0.05). Furthermore, an increased amount of bile salts was released in portal blood and extracted by the remnant liver (P < 0.05). Postoperatively, bile salt levels were elevated from day 1 onward (P < 0.001). For FGF19, intra-operative or postoperative changes of ΔVA or plasma levels were not observed. The bile salt-homeostatic regulator farnesoid X receptor (FXR) was markedly up-regulated following surgery (P < 0.001). Cell-cycle re-entry priming factors (interleukin 6 [IL-6], signal transducer and activator of transcription 3 [STAT3], and cJUN) were up-regulated following surgery and were positively correlated with FXR expression (P < 0.05). Postoperative hyperbilirubinemia was preceded by postsurgery low FXR and high Na+/Taurocholate cotransporting polypeptide (NTCP) expression in the remnant liver coupled with higher liver bile salt content (P < 0.05). Finally, bile salt levels on postoperative day 1 were an independent predictor of LR (P < 0.05). Conclusion: Systemic, portal, and liver bile salt levels are rapidly elevated after liver resection. Postoperative bile salts were positively associated with liver volume gain. In the studied time frame, FGF19 levels remained unaltered, suggesting that FGF19 plays a minor role in human LR. These findings indicate a more relevant role of bile salts in human LR.
| S-EPMC8369949 | biostudies-literature
Project description:This study aimed to investigate the role of the gut microbiota (GM)-bile acid (BA)-fibroblast growth factor (FGF) 19 axis in patients with atrial fibrillation (AF). Gut bacterial metabolisms of BAs were determined in an AF metagenomic dataset. The composition of faecal BAs pools was characterized by targeted metabolomics in an independent AF cross-sectional cohort. Circulating levels of FGF19 were measured by ELISA. In vitro cell experiments were conducted to validate the regulatory role of FGF19 in atrial cardiomyocytes stimulated with palmitic acid. First, metagenomic profiling revealed that gut microbial biotransformation from primary to secondary BAs was dysregulated in AF patients. Second, the proportion of secondary BAs decreased in the faeces of patients with AF. Also, eight BAs were identified as AF-associated BAs, including seven AF-enriched BAs (ursodeoxycholic acid, chenodeoxycholic acid, etc.), and AF-decreased dehydrolithocholic acid. Third, reduced levels of circulating FGF19 were observed in patients with AF. Subsequently, FGF19 was found to protect against palmitic acid-induced lipid accumulation and dysregulated signalling in atrial cardiomyocytes, including attenuated phosphorylation of YAP and Ca2+ /calmodulin-dependent protein kinases II and secretion of interleukin-1β, mediated via peroxisome proliferator-activated receptor α. Our data found decreased levels of secondary BAs and circulating FGF19, resulting in the impaired protective function of FGF19 against lipid accumulation in atrial cardiomyocytes.
| S-EPMC10623955 | biostudies-literature
Project description:Farnesoid-X-Receptor (FXR) plays a central role in maintaining bile acid (BA) homeostasis by transcriptional control of numerous enterohepatic genes, including intestinal FGF19, a hormone that strongly represses hepatic BA synthesis. How activation of the FGF19 receptor at the membrane is transmitted to the nucleus for transcriptional regulation of BA levels and whether FGF19 signaling posttranslationally modulates FXR function remain largely unknown. Here we show that FXR is phosphorylated at Y67 by non-receptor tyrosine kinase, Src, in response to postprandial FGF19, which is critical for its nuclear localization and transcriptional regulation of BA levels. Liver-specific expression of phospho-defective Y67F-FXR or Src downregulation in mice results in impaired homeostatic responses to acute BA feeding, and exacerbates cholestatic pathologies upon drug-induced hepatobiliary insults. Also, the hepatic FGF19-Src-FXR pathway is defective in primary biliary cirrhosis (PBC) patients. This study identifies Src-mediated FXR phosphorylation as a potential therapeutic target and biomarker for BA-related enterohepatic diseases.
| S-EPMC6030054 | biostudies-literature
Project description:The farnesoid X receptor (Fxr) controls bile acid homeostasis by coordinately regulating the expression of synthesizing enzymes (Cyp7a1, Cyp8b1), conjugating enzymes (Bal, Baat) and transporters in the ileum (Asbt, Ostα/β) and liver (Ntcp, Bsep, Ostβ). Transcriptional regulation by Fxr can be direct, or through the ileal Fgf15/FGF19 and hepatic Shp pathways. Circulating bile acids are increased during pregnancy due to hormone-mediated disruption of Fxr signaling. While this adaptation enhances lipid absorption, elevated bile acids may predispose women to develop maternal cholestasis. The objective of this study was to determine whether short-term treatment of pregnant mice with GW4064 (a potent FXR agonist) restores Fxr signaling to the level observed in virgin mice. Plasma, liver and ilea were collected from virgin and pregnant mice administered vehicle or GW4064 by oral gavage. Treatment of pregnant mice with GW4064 induced ileal Fgf15, Shp and Ostα/β mRNAs, and restored hepatic Shp, Bal, Ntcp, and Bsep back to vehicle-treated virgin levels. Pregnant mice exhibited 2.5-fold increase in Cyp7a1 mRNA compared to virgin controls, which was reduced by GW4064. Similarly treatment of mouse primary hepatocytes with plasma isolated from pregnant mice induced Cyp7a1 mRNA by nearly 3-fold as compared to virgin plasma, which could be attenuated by co-treatment with either GW4064 or recombinant FGF19 protein. Collectively, these data reveal that repressed activity of intestinal and hepatic Fxr in pregnancy, as previously demonstrated, may be restored by pharmacological activation. This study provides the basis for a novel approach to restore bile acid homeostasis in patients with maternal cholestasis.
| S-EPMC5064858 | biostudies-literature
Project description:Nonalcoholic fatty liver disease (NAFLD) is an increasingly prevalent chronic liver disease for which no approved therapies are available. Despite intensive research, the cellular mechanisms that mediate NAFLD pathogenesis and progression are poorly understood. Although obesity, diabetes, insulin resistance, and related metabolic syndrome, all consequences of a Western diet lifestyle, are well-recognized risk factors for NAFLD development, dysregulated bile acid metabolism is emerging as a novel mechanism contributing to NAFLD pathogenesis. Notably, NAFLD patients exhibit a deficiency in fibroblast growth factor 19 (FGF19), an endocrine hormone in the gut-liver axis that controls de novo bile acid synthesis, lipogenesis, and energy homeostasis. Using a mouse model that reproduces the clinical progression of human NAFLD, including the development of simple steatosis, nonalcoholic steatohepatitis (NASH), and advanced "burnt-out" NASH with hepatocellular carcinoma, we demonstrate that FGF19 as well as an engineered nontumorigenic FGF19 analogue, M70, ameliorate bile acid toxicity and lipotoxicity to restore liver health. Mass spectrometry-based lipidomics analysis of livers from mice treated with FGF19 or M70 revealed significant reductions in the levels of toxic lipid species (i.e., diacylglycerols, ceramides and free cholesterol) and an increase in levels of unoxidized cardiolipins, an important component of the inner mitochondrial membrane. Furthermore, treatment with FGF19 or M70 rapidly and profoundly reduced levels of liver enzymes, resolved the histologic features of NASH, and enhanced insulin sensitivity, energy homeostasis, and lipid metabolism. Whereas FGF19 induced hepatocellular carcinoma formation following prolonged exposure in these mice, animals expressing M70 showed no evidence of liver tumorigenesis in this model. Conclusion: We have engineered an FGF19 hormone that is capable of regulating multiple pathways to deliver antisteatotic, anti-inflammatory, and antifibrotic activities and that represents a potentially promising therapeutic for patients with NASH. (Hepatology Communications 2017;1:1024-1042).
| S-EPMC5721409 | biostudies-literature
Project description:Fibroblast growth factor 19 (FGF19) is a hormone-like protein that regulates carbohydrate, lipid and bile acid metabolism. At supra-physiological doses, FGF19 also increases hepatocyte proliferation and induces hepatocellular carcinogenesis in mice. Much of FGF19 activity is attributed to the activation of the liver enriched FGF Receptor 4 (FGFR4), although FGF19 can activate other FGFRs in vitro in the presence of the coreceptor ?Klotho (KLB). In this report, we investigate the role of FGFR4 in mediating FGF19 activity by using Fgfr4 deficient mice as well as a variant of FGF19 protein (FGF19v) which is specifically impaired in activating FGFR4. Our results demonstrate that FGFR4 activation mediates the induction of hepatocyte proliferation and the suppression of bile acid biosynthesis by FGF19, but is not essential for FGF19 to improve glucose and lipid metabolism in high fat diet fed mice as well as in leptin-deficient ob/ob mice. Thus, FGF19 acts through multiple receptor pathways to elicit pleiotropic effects in regulating nutrient metabolism and cell proliferation.
| S-EPMC3060878 | biostudies-other