Discovery of dipeptidyl peptidase-4 inhibitor specific biomarker in non-alcoholic fatty liver disease mouse models using modified basket trial.
Clin Mol Hepatol
; 28(3): 497-509, 2022 07.
Article
em En
| MEDLINE
| ID: mdl-35484644
ABSTRACT
BACKGROUND/AIMS:
We aimed to define an optimal target population and drug-specific biomarkers that may predict dipeptidyl peptidase (DPP)-4 inhibitor responses in non-alcoholic fatty liver disease (NAFLD).METHODS:
An exploration study (study I) was performed using three different NAFLD models (basket study design; high-fat diet [HFD], methionine choline-deficient diet [MCD], and high-cholesterol Western diet [WD] models). RNA transcriptome analysis was performed on pre-studied liver tissues to identify biomarkers that could predict the response to DPP-4 inhibitors. In the validation study (study II), the HFD-induced NAFLD model was divided into high and low hepatic insulin-like growth factor binding protein 1 (Igfbp-1) groups based on the pre-study liver biopsy.RESULTS:
DPP-4 inhibitor attenuated the NAFLD activity score and fibrosis stage in the HFD model but not in the WD and MCD models. The overall response rate was 19% across the modified basket NAFLD trial and 42%, 25%, and 0% in the HFD, WD, and MCD models. Hepatic Igfbp-1 expression was higher in the responder group than in the non-responder group in pre-study biopsy samples. In contrast, hepatic Igfbp-1 expression was lower in the responder group than in the non-responder group in the end-study biopsy samples. DPP-4 inhibitor response rates were 83% and 17% in the baseline hepatic high Igfbp-1 and low Igfbp-1 groups, respectively. Hepatic messenger RNA Igfbp-1 expression was positively correlated with serum IGFBP-1 levels.CONCLUSION:
The DPP-4 inhibitor response was higher in the HFD phenotype and pre-treatment levels of hepatic or serum IGFBP-1 were high.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Temas:
Geral
Base de dados:
MEDLINE
Assunto principal:
Inibidores da Dipeptidil Peptidase IV
/
Hepatopatia Gordurosa não Alcoólica
Tipo de estudo:
Diagnostic_studies
/
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Clin Mol Hepatol
Ano de publicação:
2022
Tipo de documento:
Article