Bile acids in nonalcoholic steatohepatitis: Pathophysiological driving force or innocent bystanders?

Jahn, Daniel; Geier, Andreas

doi:10.1002/hep.29543

Cited by 17 publications

(22 citation statements)

References 10 publications

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“…However, there is currently no explanation for the alterations in BAs composition in blood, the decreased ratio of secondary/primary BAs observed by us (Extended Data Fig. 7) and others 42,44,51 , and whether it correlates with changes in tissue morphology 44 . Our data shed new light on this problem.…”

Section: Discussionmentioning

confidence: 67%

“…During the last years, there has been an enormous interest in getting a better understanding of NAFLD establishment and progression due to its growing impact on public health 41 . A lot of attention has been mostly drawn to the role of signalling pathways 42-44 , microbiome 45,46 , metabolism 47 , genetic risk factors 48 , BAs 44 , etc. However, a major challenge is to understand how the molecular alterations detected are expression of the organ dysfunction, manifested as morphological and functional alterations of cells and tissue architecture.…”

Section: Discussionmentioning

confidence: 99%

“…The altered BC microanatomy and the consequent increase in bile pressure in the pericentral zone suggest that STEA and eNASH livers are affected by a pericentral cholestasis which may contribute to the changes in BA composition observed in NAFLD 42,44,51 . Unimpaired bile flow is essential for normal liver function.…”

Section: Discussionmentioning

confidence: 99%

“…In recent years, a lot of research has been devoted to the role of BAs and the activity of their receptor FXR, in NAFLD 42-44 . However, there is currently no explanation for the alterations in BAs composition in blood, the decreased ratio of secondary/primary BAs observed by us (Extended Data Fig.…”

Section: Discussionmentioning

confidence: 99%

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3D spatially-resolved geometrical and functional models of human liver tissue reveal new aspects of NAFLD progression

Segovia-Miranda

Morales‐Navarrete

Kücken

et al. 2019

Preprint

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25Early disease diagnosis is key for the effective treatment of diseases. It relies on the 26 identification of biomarkers and morphological inspection of organs and tissues. 27Histopathological analysis of human biopsies is the gold standard to diagnose tissue 28 alterations. However, this approach has low resolution and overlooks 3D structural changes 29 that are consequence of functional alterations. Here, we applied multiphoton imaging, 3D 30 digital reconstructions and computational simulations to generate spatially-resolved 31 geometrical and functional models of human liver tissue at different stages of non-alcoholic 32 fatty liver disease (NAFLD). We identified a set of new morphometric cellular parameters 33 correlated with disease progression. Moreover, we found profound topological defects in the 34 3D bile canaliculi (BC) network. Personalized biliary fluid dynamic simulations predicted an 35 increased pericentral biliary pressure and zonated cholestasis, consistent with elevated 36 cholestatic biomarkers in patients' sera. Our spatially-resolved models of human liver tissue 37 can contribute to high-definition medicine by identifying quantitative multi-parametric cellular 38 and tissue signatures to define disease progression and provide new insights into NAFLD 39 pathophysiology. 42High definition medicine is emerging as an integrated approach to profile and restore 43 the health of an individual using a pipeline of multi-parametric analytical and therapeutic 44 technologies 1 . High-definition medicine relies on large data sets, e.g. genomics, 45 metabolomics, to characterize human health at the molecular level. It also relies on imaging, 46 image analysis and computational modelling approaches to identify structural and functional 47 abnormalities in organs and tissues associated with a disease state. Histology has been 48 classically used to characterize tissue structure and remains the method of choice to 49 describe and monitor a large variety of pathologies 2 . However, this technique has several 50 disadvantages, e.g. it is subjective (depends on the pathologist's skills), is often semi-51 quantitative and provides only two-dimensional (2D) information, i.e. does not account for 52 the three-dimensional (3D) complexity of tissues 3 . In recent years, an increasing number of 53 studies have highlighted the importance of considering 3D information for the 54 histopathological examination of tissues 4-7 . This is particularly crucial for the analysis of 3D 55 structures. The liver is a pertinent example of an organ with a complex 3D tissue 56 organization 8 . It consists of functional units, the liver lobule 9,10 , containing two intertwined 57 networks, the sinusoids for blood flow and the bile canaliculi (BC) for bile secretion and flux 9 . 58 Sinusoids and BC run antiparallel along the central vein (CV)-portal vein (PV) axis. The 59 hepatocytes are the major parenchymal cells and display a peculiar and unique type of cell 60 polarity distinct from that of simple epithelia 11 . Whereas in epit...

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Section: Discussionmentioning

confidence: 67%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

3D spatially-resolved geometrical and functional models of human liver tissue reveal new aspects of NAFLD progression

Segovia-Miranda

Morales‐Navarrete

Kücken

et al. 2019

Preprint

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“…Precise signaling and molecular mechanisms operating in this shunt remain to be explored. Whatever the mechanisms involved in the control of BA pool hydrophobicity in humans (whether dependent or not on TGR5), our data on hepatectomized patients suggest that BA composition is critical for liver repair in both mice and humans, this concept being still debated [29,30].…”

Section: Discussionmentioning

confidence: 90%

Bile Acid pool composition and Gallbladder function are controlled by TGR5 to protect the liver against Bile Acid overload

Bidault

Merlen

Glénisson

et al. 2020

Preprint

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Backgrounds & AimsAs the bile acid (BA) pool composition is of major impact on liver pathophysiology, we studied its regulation by the BA receptor TGR5, promoting hepatoprotection against BA overload.MethodsWT, total and hepato-specific TGR5-KO, and TGR5-overexpressing mice were used in: partial and 90% extended hepatectomies (EH) upon normal, ursodeoxycholic acid (UDCA)- or cholestyramine (CT)-enriched diet, bile duct ligation (BDL), cholic acid (1%)-enriched diet, and TGR5 agonist (RO) treatments. We thereby studied TGR5 impact on: BA pool composition, liver injury, regeneration and survival. Particular focus was made on gut microbiota (GM) and gallbladder (GB) function analysis. BA pool composition was analyzed in patients undergoing major hepatectomy.ResultsThe TGR5-KO hyperhydrophobic BA pool was not related to BA synthesis alteration, nor to the TGR5-KO GM dysbiosis, as supported by hepatocyte-specific KO mice and cohousing experiments. The TGR5-dependent control of GB dilatation was crucial for BA pool composition, as determined by experiments including RO treatment +/− cholecystectomy. The poor TGR5-KO post-EH survival rate, related with exacerbated peribiliary necrosis and BA overload, was improved by shifting the BA pool towards a more hydrophilic composition (CT and UDCA treatments). After either BDL or CA-enriched diet +/− cholecystectomy, we found that GB dilatation had strong TGR5-dependent hepatoprotective properties. In patients, a more hydrophobic BA pool was correlated with an unfavorable outcome after hepatectomy.ConclusionBA pool composition is crucial for hepatoprotection in mice and humans. We point 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 patients study, this work brings some new light on the relationships between biliary homeostasis, gallbladder function and liver protection. We showed that the bile acid pool composition is crucial for optimal liver repair, not only in mice but also in human patients undergoing major hepatectomy.

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A GLP‐1/GLP‐2 receptor dual agonist to treat NASH: Targeting the gut‐liver axis and microbiome

et al. 2021

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Background and Aims Currently there is no Food and Drug Administration–approved drug to treat NAFLD and NASH, the rates of which are increasing worldwide. Although NAFLD/NASH are highly complex and heterogeneous conditions, most pharmacotherapy pipelines focus on a single mechanistic target. Considering the importance of the gut‐liver axis in their pathogenesis, we investigated the therapeutic effect of a long‐acting dual agonist of glucagon‐like peptide (GLP)‐1 and GLP‐2 receptors in mice with NAFLD/NASH. Approach and Results C57BL/6J mice were fed a choline‐deficient high‐fat diet/high fructose and sucrose solution. After 16 weeks, mice were randomly allocated to receive vehicle, GLP1‐Fc, GLP2‐Fc, or GLP1/2‐Fc fusion (GLP1/2‐Fc) subcutaneously every 2 days for 4 weeks. Body weight was monitored, insulin/glucose tolerance tests were performed, feces were collected, and microbiome profiles were analyzed. Immobilized cell systems were used to evaluate direct peptide effect. Immunohistochemistry, quantitative PCR, immunoblot analysis, tunnel assay, and biochemical assays were performed to assess drug effects on inflammation, hepatic fibrosis, cell death, and intestinal structures. The mice had well‐developed NASH phenotypes. GLP1/2‐Fc reduced body weight, glucose levels, hepatic triglyceride levels, and cellular apoptosis. It improved liver fibrosis, insulin sensitivity, and intestinal tight junctions, and increased microvillus height, crypt depth, and goblet cells of intestine compared with a vehicle group. Similar effects of GLP1/2‐Fc were found in in vitro cell systems. GLP1/2‐Fc also changed microbiome profiles. We applied fecal microbiota transplantation (FMT) gain further insight into the mechanism of GLP1/2‐Fc–mediated protection. We confirmed that FMT exerted an additive effect on GLP1‐Fc group, including the body weight change, liver weight, hepatic fat accumulation, inflammation, and hepatic fibrosis. Conclusions A long‐acting dual agonist of GLP‐1 and GLP‐2 receptors is a promising therapeutic strategy to treat NAFLD/NASH.

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Bile acids in nonalcoholic steatohepatitis: Pathophysiological driving force or innocent bystanders?

Cited by 17 publications

References 10 publications

3D spatially-resolved geometrical and functional models of human liver tissue reveal new aspects of NAFLD progression

3D spatially-resolved geometrical and functional models of human liver tissue reveal new aspects of NAFLD progression

Bile Acid pool composition and Gallbladder function are controlled by TGR5 to protect the liver against Bile Acid overload

A GLP‐1/GLP‐2 receptor dual agonist to treat NASH: Targeting the gut‐liver axis and microbiome

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