Potential of ileal bile acid transporter inhibition as a therapeutic target in Alagille syndrome and progressive familial intrahepatic cholestasis

Kamath, Binita M.; Stein, Philip; Houwen, Roderick H. J.; Verkade, Henkjan J.

doi:10.1111/liv.14553

Cited by 46 publications

(50 citation statements)

References 85 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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“…In humans, ASBT inhibition also lowers plasma LDL-c levels (9,36,37). However, due to the effectiveness of cholesterol lowering drugs such as statins and BA sequestrants, research on the therapeutic use of ASBT inhibitors shifted to treatment of chronic constipation and (pruritis associated with) cholestatic disorders (23,31). Recently, ASBT inhibition has also been reported to improve NAFLD, glucose metabolism and lipid metabolism (7).…”

Section: Metabolic Consequences Of Ileal Interruption Of the Enterohepatic Circulation Of Bile Acidsmentioning

confidence: 99%

Metabolic consequences of ileal interruption of the enterohepatic circulation of bile acids

Peppel

Verkade

Jonker

2020

American Journal of Physiology-Gastrointestinal and Liver Physi

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The enterohepatic circulation of bile acids comprises a tightly regulated process of hepatic bile acid secretion, intestinal reabsorption and transport back to the liver. Disruption of this process has significant consequences for both gastrointestinal, liver and whole-body homeostasis and therefore offers opportunities for therapeutic intervention. In this review we discuss the effects of (pharmacological) interruption of the enterohepatic circulation at different levels. Recently, several studies have been published on ileal interruption of the enterohepatic circulation of bile acids, targeting the apical-sodium dependent bile acid transporter (ASBT, SLC10A2), as therapy for various diseases. However, ambiguous results have been reported and in-depth mechanistic insights are lacking. Here we discuss these novel studies and review the current knowledge and literature on the consequences of ASBT inhibition and its potential effects on physiology and metabolism.

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“…Excessive accumulation of bile acids can lead to hepatobiliary change like cholestasis ( 68 ). SULT-mediated sulfonation is an important pathway to maintain the bile acid homeostasis ( 69 ).…”

Section: Discussionmentioning

confidence: 99%

Structure of mouse cytosolic sulfotransferase SULT2A8 provides insight into sulfonation of 7α-hydroxyl bile acids

Wang

Chan

et al. 2021

Journal of Lipid Research

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Cytosolic sulfotransferases (SULTs) catalyze the transfer of a sulfonate group from the cofactor 3'-phosphoadenosine 5'-phosphosulfate to a hydroxyl (OH) containing substrate and play a critical role in the homeostasis of endogenous compounds, including hormones, neurotransmitters, and bile acids. In human, SULT2A1 sulfonates the 3-OH of bile acids; however, bile acid metabolism in mouse is dependent on a 7α-OH sulfonating SULT2A8 via unknown molecular mechanisms. In this study, the crystal structure of SULT2A8 in complex with adenosine 3',5'-diphosphate and cholic acid was resolved at a resolution of 2.5 Å. Structural comparison with human SULT2A1 reveals different conformations of substrate binding loops. In addition, SULT2A8 possesses a unique substrate binding mode that positions the target 7α-OH of the bile acid close to the catalytic site. Furthermore, mapping of the critical residues by mutagenesis and enzyme activity assays further highlighted the importance of Lys44 and His48 for enzyme catalysis and Glu237 in loop 3 on substrate binding and stabilization. In addition, limited proteolysis and thermal shift assays suggested that the cofactor and substrates have protective roles in stabilizing SULT2A8 protein.Together, the findings unveil the structural basis of bile acid sulfonation targeting 7α-OH and shed light on the functional diversity of bile acid metabolism across species.Supplementary key words bile acid metabolism • protein structure • homeostasis • liver • sulfotransferase • mSULT2A8 • X-ray crystallography • 7-hydroxyl • sulfonation

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Potential of ileal bile acid transporter inhibition as a therapeutic target in Alagille syndrome and progressive familial intrahepatic cholestasis

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 46 publications

References 85 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

Metabolic consequences of ileal interruption of the enterohepatic circulation of bile acids

Structure of mouse cytosolic sulfotransferase SULT2A8 provides insight into sulfonation of 7α-hydroxyl bile acids

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