Dataset Information

Bile acid flux is necessary for normal liver regeneration.

ABSTRACT:

Background & aims

Many signals governing liver regeneration (LR) following 2/3 partial hepatectomy (PH) are recognized, but the primary signal(s) remains unknown. The aim of the study was to confirm that the remnant liver after PH lacks capacity to secrete the BA pool returning via the enterohepatic ciruculation (EHC), which may in turn stimulate LR.

Methods

After standard PH, BA flux was documented and BA signaling (Fgf15) and synthesis (Cyp7a) determined by qPCR. Rat biliary fistula (BF) and Asbt knockout mouse models interrupted the EHC prior to PH, and standard assays for LR employed along with complete RNA sequencing. CCl4 intoxication after BF tested the hypothesis in an alternate injury model.

Results

BA rise in systemic blood immediately following PH, confirming that the remnant liver cannot handle the BA returning via portal circulation. When the BA pool is drained prior to PH in the rat BF model, LR is markedly attenuated, a phenomenon reversed with duodenal BA replacement. Hepatocyte proliferation is similarly attenuated after PH in the Asbt knockout mouse as well as after CCl44 intoxication in rats with BF. Complete RNA sequencing in the rat PH model shows that early c-jun and AP-1 gene expression pathways are down regulated in the absence of BA, coincident with attenuated LR.

Conclusions

Absent BA return to the liver after PH or CCl4 injury markedly attenuates LR, though hepatocyte proliferation still occurs, inferring that BA flux and signaling are not the sole signals governing LR. Transcriptional networks involving c-jun and AP-1 are involved in the BA-specific effects on hepatocyte proliferation.

SUBMITTER: Naugler WE

PROVIDER: S-EPMC4026228 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Bile acid flux is necessary for normal liver regeneration.

Naugler Willscott E WE

PloS one 20140519 5

<h4>Background & aims</h4>Many signals governing liver regeneration (LR) following 2/3 partial hepatectomy (PH) are recognized, but the primary signal(s) remains unknown. The aim of the study was to confirm that the remnant liver after PH lacks capacity to secrete the BA pool returning via the enterohepatic ciruculation (EHC), which may in turn stimulate LR.<h4>Methods</h4>After standard PH, BA flux was documented and BA signaling (Fgf15) and synthesis (Cyp7a) determined by qPCR. Rat biliary fis ...[more]

PMID: 24841254

Similar Datasets

Project description:BackgroundCholestatic liver diseases are characterized by an accumulation of toxic bile acids (BA) in the liver, blood and other tissues which lead to progressive liver injury and poor prognosis in patients.AimTo discover and validate prognostic biomarkers of cholestatic liver diseases based on the urinary BA profile.MethodsWe analyzed urine samples by liquid chromatography-tandem mass spectrometry and investigated the use of the urinary BA profile to develop survival models that can predict the prognosis of hepatobiliary diseases. The urinary BA profile, a set of non-BA parameters, and the adverse events of liver transplant and/or death were monitored in 257 patients with cholestatic liver diseases for up to 7 years. The BA profile was characterized by calculating BA indices, which quantify the composition, metabolism, hydrophilicity, formation of secondary BA, and toxicity of the BA profile. We have developed and validated the bile-acid score (BAS) model (a survival model based on BA indices) to predict the prognosis of cholestatic liver diseases.ResultsWe have developed and validated a survival model based on BA (the BAS model) indices to predict the prognosis of cholestatic liver diseases. Our results demonstrate that the BAS model is more accurate and results in higher true-positive and true-negative prediction of death compared to both non-BAS and model for end-stage liver disease (MELD) models. Both 5- and 3-year survival probabilities markedly decreased as a function of BAS. Moreover, patients with high BAS had a 4-fold higher rate of death and lived for an average of 11 mo shorter than subjects with low BAS. The increased risk of death with high vs low BAS was also 2-4-fold higher and the shortening of lifespan was 6-7-mo lower compared to MELD or non-BAS. Similarly, we have shown the use of BAS to predict the survival of patients with and without liver transplant (LT). Therefore, BAS could be used to define the most seriously ill patients, who need earlier intervention such as LT. This will help provide guidance for timely care for liver patients.ConclusionThe BAS model is more accurate than MELD and non-BAS models in predicting the prognosis of cholestatic liver diseases.

Project description:Background & aimsAs the composition of the bile acid (BA) pool has a major impact on liver pathophysiology, we studied its regulation by the BA receptor Takeda G protein coupled receptor (TGR5), which promotes hepatoprotection against BA overload.MethodsWild-type, total and hepatocyte-specific TGR5-knockout, and TGR5-overexpressing mice were used in: partial (66%) and 89% extended hepatectomies (EHs) upon normal, ursodeoxycholic acid (UDCA)- or cholestyramine (CT)-enriched diet, bile duct ligation (BDL), cholic acid (CA)-enriched diet, and TGR5 agonist (RO) treatments. We thereby studied the impact of TGR5 on: BA composition, liver injury, regeneration and survival. We also performed analyses on the gut microbiota (GM) and gallbladder (GB). Liver BA composition was analysed in patients undergoing major hepatectomy.ResultsThe TGR5-KO hyperhydrophobic BA composition was not directly related to altered BA synthesis, nor to TGR5-KO GM dysbiosis, as supported by hepatocyte-specific KO mice and co-housing experiments, respectively. The TGR5-dependent control of GB dilatation was crucial for BA composition, as determined by experiments including RO treatment and/or cholecystectomy. The poor TGR5-KO post-EH survival rate, related to exacerbated peribiliary necrosis and BA overload, was improved by shifting BAs toward a less toxic composition (CT treatment). After either BDL or a CA-enriched diet with or without cholecystectomy, we found that GB dilatation had strong TGR5-dependent hepatoprotective properties. In patients, a more hydrophobic liver BA composition was correlated with an unfavourable outcome after hepatectomy.ConclusionsBA composition is crucial for hepatoprotection in mice and humans. We indicate TGR5 as a key regulator of BA profile and thereby as a potential hepatoprotective target under BA overload conditions.Lay summaryThrough multiple in vivo experimental approaches in mice, together with a patient study, this work brings some new light on the relationships between biliary homeostasis, gallbladder function, and liver protection. We showed that hepatic bile acid composition is crucial for optimal liver repair, not only in mice, but also in human patients undergoing major hepatectomy.

Dataset Information

Bile acid flux is necessary for normal liver regeneration.

Background & aims

Methods

Results

Conclusions

Publications

Bile acid flux is necessary for normal liver regeneration.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets