Clin Mol Hepatol.  2022 Jul;28(3):497-509. 10.3350/cmh.2022.0019.

Discovery of dipeptidyl peptidase-4 inhibitor specific biomarker in non-alcoholic fatty liver disease mouse models using modified basket trial

• Oh JH
• Jun DW
• Kim HY
• Lee SM
• Yoon EL
• Hwang J
• Park JH
• Lee H
• Kim W
• Kim H

• KMID: 2531374
• DOI: http://doi.org/10.3350/cmh.2022.0019

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.
Conclusions
The DPP-4 inhibitor response was higher in the HFD phenotype and pre-treatment levels of hepatic or serum IGFBP-1 were high.

Keyword

Biopsy; Nonalcoholic fatty liver disease; Dipeptidyl peptidase 4 inhibitor; Insulin-like growth factor binding protein 1; Biomarker