Novel therapeutic targets in primary biliary cirrhosis

Dyson, Jessica; Hirschfield, Gideon M.; Adams, David H.; Beuers, Ulrich; Mann, Derek A.; Lindor, Keith D.; Jones, David

doi:10.1038/nrgastro.2015.12

Cited by 113 publications

(103 citation statements)

References 138 publications

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“…Generally speaking, therapeutic opportunities in PBC or PSC are offered by targeting the so-called 'upstream' immune response, 'midstream' biliary injury leading to cholestasis and 'downstream' fibrotic processes [25] . Novel therapeutic approaches targeting primarily cholestasis include (i) agonists of nuclear receptors: farnesoid X receptor (FXR), retinoid X receptor, pregnane X receptor (PXR), glucocorticoid receptor (GR), peroxisome proliferator-activated receptor α (PPARα) and vitamin D receptor (VDR) that are transcriptional modifiers of bile formation, (ii) agonists of TGR5, a BA membrane recep- tor expressed in various tissues, (iii) inhibitors of the ileal apical sodium BA transporter (ASBT), (iv) derivatives of the FXR-induced fibroblast growth factor 19 (FGF19) from the ileum that suppresses hepatic BA synthesis and (v) nor UDCA, a 23-C homologue of UDCA with specific physicochemical and therapeutic properties [26] .…”

Section: Novel Potential Therapeutic Approaches In Cholestatic Disordersmentioning

confidence: 99%

Novel Aspects in the Management of Cholestatic Liver Diseases

Chazouillères¹

2016

Dig Dis

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Background: There is a great need for risk stratification in patients with chronic cholestatic diseases in order to allow for more personalized care and adapted management as well as for well-designed therapeutic trials. Novel tools for monitoring primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) patients have been recently proposed. In addition, major insight has been gained into bile acid (BA) physiology during the last decade including the role of BAs as metabolic modulators and the gut-liver axis. As a consequence, alongside drugs targeting immune response or fibrotic processes, a number of novel anti-cholestatic agents have undergone pre-clinical and clinical evaluation and have shown promising results although none has been approved yet. Key Messages: Biochemical non-response to ursodeoxycholic acid (UDCA) (mainly defined by bilirubin and alkaline phosphatase levels at 1 year) is a strong prognostic factor in PBC whereas present biochemical surrogates are far from robust in PSC. By contrast, liver stiffness measurement by vibration-controlled transient elastography (VCTE) is a very promising tool in both PBC and PSC. Novel therapeutic approaches include (i) agonists of nuclear receptors, especially farnesoid X receptor (FXR), pregnane X receptor (PXR), glucocorticoid receptor (GR) and peroxisome proliferator-activated receptor α (PPARα) that are transcriptional modifiers of bile formation; (ii) agonists of TGR5, a BA membrane receptor expressed in various tissues; (iii) inhibitors of the ileal apical sodium BA transporter; (iv) derivatives of the FXR-induced fibroblast growth factor 19 from the ileum that suppresses hepatic BA synthesis and (v) norUDCA, a side chain shortened UDCA derivative with specific physicochemical and therapeutic properties. The most advanced clinical evaluation (PBC patients) relates to agonists for PPARα, FXR and GR/PXR most often in combination with UDCA, namely fibrates, obeticholic acid (OCA) and budesonide, respectively. Existing results look promising even though some side effects are worrisome such as pruritus in OCA-treated patients. Results of large well-designed studies are eagerly awaited. Conclusions: Major advances in the management of cholestatic liver diseases are in progress and promising times for these patients seem likely in the near future.

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Section: Novel Potential Therapeutic Approaches In Cholestatic Disordersmentioning

confidence: 99%

Novel Aspects in the Management of Cholestatic Liver Diseases

Chazouillères¹

2016

Dig Dis

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“…9,10 The primary autoantigen of PBC has been identified as the E2 subunit of the pyruvate dehydrogenase complex (PDC-E2). [11][12][13][14][15] Data from human studies and animal models demonstrate that the pathogenesis of PBC involves not only autoreactive T cells and other immune cells [16][17][18][19][20][21][22] but also biliary epithelial cells. 12,18,19,[23][24][25][26][27][28][29][30] Herein, we demonstrate that circulating exosomes from PBC could be taken up by antigenpresenting cells (APCs) and affect the expression of cell surface co-stimulatory molecules.…”

Section: Introductionmentioning

confidence: 99%

The modulation of co-stimulatory molecules by circulating exosomes in primary biliary cirrhosis

et al. 2015

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Exosomes are nanoparticles of endocytic origin, secreted by a myriad of cell populations that are attracting increased attention by virtue of their ability to modulate cell-to-cell communications. They are also attracting attention in a variety of immunological issues, including autoimmunity and, in particular, their ability to regulate cytokine and chemokine activation. Primary biliary cirrhosis (PBC) is considered a model autoimmune disease, which has a highly focused cytotoxic response against biliary epithelial cells. We have isolated exosomes from plasma from 29 patients with PBC and 30 healthy controls (HCs), and studied the effect of these exosomes on co-stimulatory molecule expression and cytokine production in mononuclear cell populations using an ex vivo system. We also identified the microRNA (miRNA) populations in PBC compared to HC exosomes. We report herein that although exosomes do not change cytokine production, they do significantly alter co-stimulatory molecule expression on antigen-presenting populations. Further, we demonstrated that CD86 up-regulated expression on CD14 1 monocytes, whereas CD40 up-regulated on CD11c 1 dendritic cells by exosomes from patients with PBC. In addition, there were differences of miRNA expression of circulating exosomes in patients with PBC. These data have significant importance based on observations that co-stimulatory molecules play a differential role in the regulation of T-cell activation. Our observation indicated that aberrant exosomes from PBC selectively induce expression of co-stimulatory molecules in different subset of antigen-presenting cells. These alterations may involve in pathogenesis of autoimmune liver disease. Cellular & Molecular Immunology

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“…The development of an effective therapy, therefore, awaits new insights into the disease mechanism and identification of its etiology. Readers are referred to a recent review by Dyson et al [52] for potential novel therapeutic targets in different aspects of PBC from aberrant immune response, cholestatic injury, fibrosis to itch and fatigue.…”

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The Emerging Role of Soluble Adenylyl Cyclase in Primary Biliary Cholangitis

Chang

Beuers²,

Elferink³

2017

Dig Dis

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Background: Primary biliary cholangitis (PBC; previously referred to as primary biliary cirrhosis) is a chronic fibrosing cholangiopathy with the signature of an autoimmune disease and features of intrahepatic cholestasis. Immunosuppressing treatments are largely unsuccessful. Responsiveness to ursodeoxycholic acid and reduced expression of anion exchanger 2 (AE2) on canalicular membranes and small bile ducts underline the importance of bicarbonate transportation in its disease mechanism. Soluble adenylyl cyclase (sAC; ADCY10) is an evolutionarily conserved bicarbonate sensor that regulates apoptosis, barrier function and TNF signaling. Key Messages: The biliary epithelium defends against the toxic bile by bicarbonate secretion and by maintaining a tight barrier. Passive diffusion of weak acid conjugates (e.g. bile salts and other toxins) across plasma membrane is pH-dependent. Reduced AE2 expression results in both reduced bicarbonate secretion and accumulation of bicarbonate in the cells. Increased intracellular bicarbonate leads to increased sAC activity, which regulates bile salt-induced apoptosis. Reduced bicarbonate secretion causes more bile salts to enter cells, which further increase sAC activity by releasing intracellular Ca²⁺ store. In vitro studies demonstrate that inhibition of sAC not only corrects sensitization to bile salt-induced apoptosis as a result of AE2 down-regulation but also prevents bile salt-induced apoptosis altogether. Targeting sAC is also likely to slow down disease progression by strengthening the barrier function of biliary epithelia and by reducing oxidative stress as a result of chronic inflammation. Conclusions: sAC is a potential therapeutic target for PBC. More in vitro and in vivo studies are needed to understand how sAC regulates bile salt-induced apoptosis and to establish its therapeutic value in PBC and other cholestatic cholangiopathies.

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Novel therapeutic targets in primary biliary cirrhosis

Cited by 113 publications

References 138 publications

Novel Aspects in the Management of Cholestatic Liver Diseases

Novel Aspects in the Management of Cholestatic Liver Diseases

The modulation of co-stimulatory molecules by circulating exosomes in primary biliary cirrhosis

The Emerging Role of Soluble Adenylyl Cyclase in Primary Biliary Cholangitis

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