Circulating indian hedgehog is a marker of the hepatocyte-TAZ pathway in experimental NASH and is elevated in humans with NASH.
Biomarker
Fibrosis
IHH
NAFLD
NASH
TAZ
Journal
JHEP reports : innovation in hepatology
ISSN: 2589-5559
Titre abrégé: JHEP Rep
Pays: Netherlands
ID NLM: 101761237
Informations de publication
Date de publication:
May 2023
May 2023
Historique:
received:
01
11
2022
revised:
08
02
2023
accepted:
11
02
2023
medline:
11
4
2023
entrez:
10
4
2023
pubmed:
11
4
2023
Statut:
epublish
Résumé
Non-alcoholic steatohepatitis (NASH)-induced liver fibrosis is emerging as the most common cause of liver disease. For evaluation of therapies, there is a pressing need to identify non-invasive, mechanism-based biomarkers. A pro-fibrotic process relevant to human NASH involves a pathway in which a transcriptional regulator called TAZ (WWTR1) in hepatocytes induces the secretion of pro-fibrotic Indian hedgehog (IHH). We therefore reasoned that circulating IHH may be a useful mechanism-based marker to assess changes in NASH fibrosis. Circulating IHH was assessed in wild-type and hepatocyte-TAZ-silenced NASH mice and in three separate cohorts of patients with mild-moderate NASH. Circulating IHH was elevated in mice with diet-induced NASH compared with chow-fed mice or with NASH mice in which hepatocyte TAZ was silenced, which is an effective means to decrease NASH fibrosis. In patients with fatty liver disease with or without NASH, NASH fibrosis was associated with increased concentrations of circulating IHH. The results of these analyses support further investigation to determine whether circulating IHH may be useful as a mechanism-based indicator of target engagement in anticipated future clinical trials testing NASH fibrosis therapies that block the IHH pathway. Non-alcoholic steatohepatitis (NASH)-induced liver fibrosis is a common cause of liver disease. Circulating biomarkers that reflect liver fibrosis in NASH would be very useful to evaluate therapies. One mechanism of NASH fibrosis with potential as a therapeutic target involves a liver-secreted protein called Indian hedgehog (IHH). We report that circulating levels of IHH in experimental and human NASH associates with NASH and NASH-associated liver fibrosis, providing the premise for further investigation into using circulating IHH to evaluate anticipated future NASH therapies that block the IHH pathway in liver.
Sections du résumé
Background & Aims
UNASSIGNED
Non-alcoholic steatohepatitis (NASH)-induced liver fibrosis is emerging as the most common cause of liver disease. For evaluation of therapies, there is a pressing need to identify non-invasive, mechanism-based biomarkers. A pro-fibrotic process relevant to human NASH involves a pathway in which a transcriptional regulator called TAZ (WWTR1) in hepatocytes induces the secretion of pro-fibrotic Indian hedgehog (IHH). We therefore reasoned that circulating IHH may be a useful mechanism-based marker to assess changes in NASH fibrosis.
Methods
UNASSIGNED
Circulating IHH was assessed in wild-type and hepatocyte-TAZ-silenced NASH mice and in three separate cohorts of patients with mild-moderate NASH.
Results
UNASSIGNED
Circulating IHH was elevated in mice with diet-induced NASH compared with chow-fed mice or with NASH mice in which hepatocyte TAZ was silenced, which is an effective means to decrease NASH fibrosis. In patients with fatty liver disease with or without NASH, NASH fibrosis was associated with increased concentrations of circulating IHH.
Conclusions
UNASSIGNED
The results of these analyses support further investigation to determine whether circulating IHH may be useful as a mechanism-based indicator of target engagement in anticipated future clinical trials testing NASH fibrosis therapies that block the IHH pathway.
Impact and implications
UNASSIGNED
Non-alcoholic steatohepatitis (NASH)-induced liver fibrosis is a common cause of liver disease. Circulating biomarkers that reflect liver fibrosis in NASH would be very useful to evaluate therapies. One mechanism of NASH fibrosis with potential as a therapeutic target involves a liver-secreted protein called Indian hedgehog (IHH). We report that circulating levels of IHH in experimental and human NASH associates with NASH and NASH-associated liver fibrosis, providing the premise for further investigation into using circulating IHH to evaluate anticipated future NASH therapies that block the IHH pathway in liver.
Identifiants
pubmed: 37035456
doi: 10.1016/j.jhepr.2023.100716
pii: S2589-5559(23)00047-2
pmc: PMC10074197
doi:
Types de publication
Journal Article
Langues
eng
Pagination
100716Informations de copyright
© 2023 The Author(s).
Déclaration de conflit d'intérêts
IT and XW have received research funding (unrestricted) from Takeda Pharmaceuticals. LV has been an invited speaker for MSD, Gilead, AlfaSigma, and AbbVie; consults for Gilead, Pfizer, Astra Zeneca, Novo Nordisk, Intercept pharmaceuticals, Diatech Pharmacogenetics, IONIS, Viatris, and Boehringer Ingelheim; and has received research funding (unrestricted) from Gilead. Please refer to the accompanying ICMJE disclosure forms for further details.
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