Ileal bile acid transporter inhibition as an anticholestatic therapeutic target in biliary atresia and other cholestatic disorders

Karpen, Saul J.; Kelly, Déirdre; Mack, Cara L.; Stein, Philip

doi:10.1007/s12072-020-10070-w

Cited by 61 publications

(47 citation statements)

References 81 publications

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“…Under normal physiological conditions, the enterohepatic circulation of bile acids is an extremely efficient process whereby bile acids are synthesized and secreted from the liver into the small intestine, with 95% subsequently being re‐absorbed and returned to the liver by the ileal bile acid transporter (IBAT; also known as the apical sodium‐dependent bile acid transporter) located in the terminal ileum 31,32 . Thus, disease manifestations in PFIC are thought to result from a subsequent toxic accumulation of bile acids that are returned to the liver and then unable to be re‐trafficked out of the hepatocyte.…”

Section: Discussionmentioning

confidence: 99%

Long‐term liver transplant outcomes for progressive familial intrahepatic cholestasis type 1: The Pittsburgh experience

Henkel

Salgado

Reyes‐Múgica

et al. 2021

Pediatric Transplantation

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Background Progressive familial intrahepatic cholestasis type 1 (PFIC1) arises from biallelic variants in the ATP8B1 gene that annul FIC1 activity, resulting in progressive liver disease. Liver transplant (LT) is indicated in refractory disease; however, post‐LT complications including worsening diarrhea and steatohepatitis progressing to fibrosis with graft loss have been reported. We aim to describe long‐term outcomes of PFIC1 LT recipients at our center, focusing on the histological changes of the allografts. Methods We assessed 7 PFIC1 patients post‐LT at the Children's Hospital of Pittsburgh (CHP). All pre‐transplant, explant, and sequential post‐transplant pathology samples were reviewed. Continuous data are presented as the mean ± SD. We compared the pre‐ and post‐transplant height and weight z‐scores using Wilcoxon signed‐rank test. Results Seven (29% male) patients with PFIC1 received a LT (n = 6) or had post‐LT care (n = 1) at CHP. Six had confirmed or suspected identical genetic. At a mean follow‐up of 10.9 years, both patient survival and graft survival were 100%. Diarrhea persisted (n = 3) or newly developed (n = 4) in all patients after LT contributing to ongoing growth failure, with mean z‐scores −2.63 (weight) and −2.98 (height) at follow‐up. Histologically, allograft steatosis was common but was not accompanied by significant inflammation, ballooning, or fibrosis. Conclusion We show that extrahepatic disease persists and near‐universal allograft steatosis occurs. However, at a mean follow‐up period of over 10 years, no patients developed steatohepatitis or significant fibrosis, and both patient survival and graft survival are excellent.

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Section: Discussionmentioning

confidence: 99%

Long‐term liver transplant outcomes for progressive familial intrahepatic cholestasis type 1: The Pittsburgh experience

Henkel

Salgado

Reyes‐Múgica

et al. 2021

Pediatric Transplantation

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“… 182 However, a recent 24-week interim analysis of a phase II trial involving ASBT inhibitor Volixibat showed that despite target affection seen by dose-dependent increase of C4 serum levels and decrease of cholesterol levels, no liver-specific therapeutic benefit could be noted. 183 Currently, a wide range of ASBT inhibitors are explored for pediatric cholestasis, but their potential benefit for NASH remains to be determined (reviewed in Karpen et al 184 ).…”

Section: Targeting Fxr In Microcholestasis Of Nash and Beyondmentioning

confidence: 99%

Role of FXR in Bile Acid and Metabolic Homeostasis in NASH: Pathogenetic Concepts and Therapeutic Opportunities

Radun

Trauner

2021

Semin Liver Dis

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Nonalcoholic fatty liver disease (NAFLD) has become the most prevalent cause of liver disease, increasingly contributing to the burden of liver transplantation. In search for effective treatments, novel strategies addressing metabolic dysregulation, inflammation, and fibrosis are continuously emerging. Disturbed bile acid (BA) homeostasis and microcholestasis via hepatocellular retention of potentially toxic BAs may be an underappreciated factor in the pathogenesis of NAFLD and nonalcoholic steatohepatitis (NASH) as its progressive variant. In addition to their detergent properties, BAs act as signaling molecules regulating cellular homeostasis through interaction with BA receptors such as the Farnesoid X receptor (FXR). Apart from being a key regulator of BA metabolism and enterohepatic circulation, FXR regulates metabolic homeostasis and has immune-modulatory effects, making it an attractive therapeutic target in NAFLD/NASH. In this review, the molecular basis and therapeutic potential of targeting FXR with a specific focus on restoring BA and metabolic homeostasis in NASH is summarized.

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“…In the ileum, the majority of bile acids is actively reabsorbed by the apical sodium-dependent bile acid transporter (ASBT, SLC10A2). Pharmacological inhibition of ASBT has been shown to effectively reduce bile acid pool and bile acid content in liver and systemic circulation and several ASBT inhibitors have already been tested in clinical trials to treat cholestatic liver diseases such as biliary atresia, progressive familial intrahepatic cholestasis and Alagille syndrome as well as chronic constipation and NASH [6,7]. The high expression and high uptake capacity of ASBT in ileum makes this transporter also a promising target for delivery of prodrugs [8].…”

Section: Bile Acid Biosynthesis Transport and Metabolismmentioning

confidence: 99%

Emerging roles of bile acids in control of intestinal functions

Yang¹,

Palmiotti²,

Kuipers

2020

Current Opinion in Clinical Nutrition &Amp; Metabolic Care

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Ileal bile acid transporter inhibition as an anticholestatic therapeutic target in biliary atresia and other cholestatic disorders

Cited by 61 publications

References 81 publications

Long‐term liver transplant outcomes for progressive familial intrahepatic cholestasis type 1: The Pittsburgh experience

Long‐term liver transplant outcomes for progressive familial intrahepatic cholestasis type 1: The Pittsburgh experience

Role of FXR in Bile Acid and Metabolic Homeostasis in NASH: Pathogenetic Concepts and Therapeutic Opportunities

Emerging roles of bile acids in control of intestinal functions

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