Systemic ASBT inactivation protects against liver damage in obstructive cholestasis in mice

Kunst, Roni F.; Waart, Dirk R. de; Wolters, Frank; Duijst, Suzanne; Vogels, Esther; Bolt, Isabelle; Verheij, Joanne; Beuers, Ulrich; Elferink, Ronald P.J. Oude; Graaf, Stan F.J. van de

doi:10.1016/j.jhepr.2022.100573

Cited by 19 publications

(15 citation statements)

References 25 publications

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“…Furthermore, as in Mdr2 −/− mice, transcriptomic analysis showed that only A3907 was able to modulate important hepatic-dysregulated processes during obstructive cholestasis (BDL), including cell growth, oxidative stress, lipid metabolism and homeostasis, and xenobiotic metabolism, among others. All these results are further supported by a previous work demonstrating that Asbt −/− mice are partially resistant to BDL-induced liver injury, linked to increased urinary BA excretion and consequently lower systemic BA levels 40 …”

Section: Discussionsupporting

confidence: 85%

“…All these results are further supported by a previous work demonstrating that Asbt −/− mice are partially resistant to BDL-induced liver injury, linked to increased urinary BA excretion and consequently lower systemic BA levels. [40] Phase I studies demonstrated that A3907 is well tolerated and shows favorable pharmacokinetics at pharmacologically active doses. Accordingly, A3907 reduced postprandial circulating levels of conjugated BAs and dose dependently increased serum C4 levels, a marker of BA synthesis downstream of CYP7A1 [41] in healthy human subjects (and in normal mice).…”

Section: Discussionmentioning

confidence: 99%

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A3907, a systemic ASBT inhibitor, improves cholestasis in mice by multiorgan activity and shows translational relevance to humans

et al. 2023

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Background and Aims: Cholestasis is characterized by intrahepatic accumulation of bile constituents, including bile acids (BAs), which promote liver damage. The apical sodium-dependent BA transporter (ASBT) plays an important role in BA reabsorption and signaling in ileum, bile ducts, and kidneys. Our aim was to investigate the pharmacokinetics and pharmacological activity of A3907, an oral and systemically available ASBT inhibitor in experimental mouse models of cholestasis. In addition, the tolerability, pharmacokinetics, and pharmacodynamics of A3907 were examined in healthy humans. Approach and Results: A3907 was a potent and selective ASBT inhibitor in vitro. In rodents, orally administered A3907 distributed to the ASBT-expressing organs, that is, ileum, liver, and kidneys, and dose dependently increased fecal BA excretion. A3907 improved biochemical, histological, and molecular markers of liver and bile duct injury in Mdr2 −/− mice and also had direct protective effects on rat cholangiocytes exposed to cytotoxic BA concentrations in vitro. In bile duct ligated mice, A3907 increased urinary BA elimination, reduced serum BA levels, and prevented body weight loss, while improving markers of liver injury. A3907 was well tolerated and demonstrated target engagement in healthy volunteers. Plasma exposure of A3907 in humans was within the range of systemic concentrations that achieved therapeutic efficacy in mouse. Conclusions: The systemic ASBT inhibitor A3907 improved experimental cholestatic disease by targeting ASBT function at the intestinal, liver, and kidney levels, resulting in marked clearance of circulating BAs and liver protection. A3907 is well tolerated in humans, supporting further clinical development for the treatment of cholestatic liver diseases.

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Section: Discussionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 99%

A3907, a systemic ASBT inhibitor, improves cholestasis in mice by multiorgan activity and shows translational relevance to humans

et al. 2023

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“…Other than the small intestine and cholangiocytes, ASBT is also expressed in the proximal renal tubule of the kidneys, where it prevents bile salts from being excreted via the urine. Systemic ASBT inactivation, to simultaneously target intestinal and renal ASBT, improves liver histology in bile duct ligated mice, and dramatically increased urinary bile salt excretion [34]. A systemic ASBT inhibitor called A3907 improved ALP, ALT and AST in Mdr2 knockout mice while it also reduced serum bile salts [35].…”

Section: Apical Sodium-dependent Bile Salt Transporter Inhibitionmentioning

confidence: 99%

Targeting bile salt homeostasis in biliary diseases

Trampert,

Kunst,

van de Graaf

2024

Current Opinion in Gastroenterology

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Purpose of review Advances in the understanding of bile salt synthesis, transport and signalling show the potential of modulating bile salt homeostasis as a therapeutic strategy in cholestatic liver diseases. Here, recent developments in (pre)clinical research in this field is summarized and discussed. Recent findings Inhibition of the apical sodium-dependent bile salt transporter (ASBT) and Na+-taurocholate cotransporting polypeptide (NTCP) seems effective against cholestatic liver diseases, as well as Farnesoid X receptor (FXR) agonism or a combination of both. While approved for the treatment of primary biliary cholangitis (PBC) and intrahepatic cholestasis of pregnancy (ICP), ursodeoxycholic acid (UDCA) has retrospectively shown carefully promising results in primary sclerosing cholangitis (PSC). The side chain shortened derivate norUDCA is of further therapeutic interest since its mechanisms of action are independent of the bile salt transport machinery. In the pathogenesis of sclerosing cholangiopathies, a skewed T-cell response with alterations in gut microbiota and bile salt pool compositions are observed. In PSC pathogenesis, the bile salt receptor Takeda G-protein-coupled receptor 5 (TGR5) in cholangiocytes is implicated, whilst in immunoglobulin G4-related cholangitis the autoantigens annexin A11 and laminin 511-E8 are involved in protecting cholangiocytes. Summary Modulating bile salt homeostasis has proven a promising treatment strategy in models of cholestasis and are continuously being further developed. Confirmatory clinical studies are needed in order to assess the proposed treatment strategies in patients allowing for a broader therapeutic arsenal in the future.

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“…The decrease of ASBT expression increases the excretion of fecal BAs and the total concentration of BAs in liver [69]. On the other hand, the interruption of BAs enterohepatic circulation which lowers their concentrations in the liver also leads to bile salt spilling over to the colon resulting in diarrhea, irregular bowel movement, and abdominal pain [70,71]. A recent study in mice found that inhibition of ASBT in the kidneys stimulates the renal bile salts excretion and consequently improving intestinal side effects [71].…”

Section: Asbt Inhibitorsmentioning

confidence: 99%

“…On the other hand, the interruption of BAs enterohepatic circulation which lowers their concentrations in the liver also leads to bile salt spilling over to the colon resulting in diarrhea, irregular bowel movement, and abdominal pain [70,71]. A recent study in mice found that inhibition of ASBT in the kidneys stimulates the renal bile salts excretion and consequently improving intestinal side effects [71]. Yet, new ASBT inhibitors like Odevixibat, Lopixibat and GSK2330672 are restricted to intestinal ASBT blockading.…”

Section: Asbt Inhibitorsmentioning

confidence: 99%

Current Therapies for Cholestatic Diseases

Méndez-Sánchez¹,

Coronel-Castillo²,

Ordoñez-Vázquez³

2023

Preprint

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Cholestasis is a condition defined as an abnormal decrease of bile flow due to progressive pathological states or cholestatic liver diseases that affect the biliary tree at intrahepatic and extrahepatic level. It induces complications such as cirrhosis, liver failure, malignancies, pruritus, fatigue, bone disease and nutritional deficiencies that merit close follow-up and specific interventions to improve quality of life. Furthermore, cholestasis can progress to end-stage liver disease and represents an entity with high morbidity and mortality; and economic burden, Therefore, it is important that clinicians understand the treatment options for cholestatic liver diseases. This review addresses the pathophysiology of cholangiopathies, a general view of current treatments and their molecular targets, and a specific review of those groups of drugs. The objective is to provide clinicians with an overview of the current treatment of cholangiopathies based on evidence on its efficacy and safety.

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Systemic ASBT inactivation protects against liver damage in obstructive cholestasis in mice

Cited by 19 publications

References 25 publications

A3907, a systemic ASBT inhibitor, improves cholestasis in mice by multiorgan activity and shows translational relevance to humans

A3907, a systemic ASBT inhibitor, improves cholestasis in mice by multiorgan activity and shows translational relevance to humans

Targeting bile salt homeostasis in biliary diseases

Current Therapies for Cholestatic Diseases

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