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

• Published in: Clinical and molecular hepatology Vol. 28; no. 3; pp. 497 - 509
• Main Authors: Ju Hee Oh, Dae Won Jun, Hye Young Kim, Seung Min Lee, Eileen L. Yoon, Jungwook Hwang, Jung Hwan Park, Hanbi Lee, Wankyu Kim, Hyunsung Kim
• Format: Journal Article
• Language: Korean
• Published: 대한간학회 01.07.2022
• Subjects: Biomarker; Biopsy; Dipeptidyl peptidase 4 inhibitor; Insulin-like growth factor binding protein 1; Nonalcoholic fatty liver disease
• ISSN: 2287-2728; 2287-285X

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. (Clin Mol Hepatol 2022;28:497-509)