There are no reports of the treatment effects of GPR119 agonists in pre-established NASH animal models yet. The aim of this study was to investigate the efficacy of DA-1241 monotherapy and to explore its combined effects with a dipeptidyl peptidase 4 (DPP-4) inhibitor in pre-established NASH mice. DA-1241 in the absence or presence of a DPP-4 inhibitor was given to biopsy-proven diet-induced NASH mice for 8 weeks. Plasma and liver tissue were tested for biochemical and/or histological analyses. Changes in gene expression profiles in the liver were evaluated by RNAseq method. Plasma profiles of a panel of cytokines were assessed. After 8-week administration, DA-1241 treatment significantly decreased hepatic lipid accumulation (-51.4%) and co-treatment of a DPP-4 inhibitor showed a further reduction (-60.6%). DA-1241 monotherapy and its combination reduced liver fibrosis score (-20.6% and -36.5%) with lower levels of hepatic type 1 collagen and plasma TIMP-1. Notably, DA-1241 alone and its combination significantly reduced the infiltration of immune cells into the liver (-25.0% and -49.1%) with drastically decreased the hepatic galectin-3 levels (-58.3% and -67.2%). Liver enzyme values decreased in both treatment groups. In line with these results, DA-1241 treatment alone prominently improved gene expression profiles associated with stellate cell activation, monocyte recruitment, inflammation signaling, and hepatocellular cell death. Moreover, plasma levels of clinically-related plasma cytokines such as CCL2, TNFα, and CXCL10 were also reduced in DA-1241-treated mice. All the effects augmented by its concomitant use with a DPP-4 inhibitor were supported by the increase of plasma active GLP-1 (6.6 folds vs. NASH control). To the best of our knowledge, this is the first report to comprehensively demonstrate the in vivo therapeutic efficacy of GPR119 agonist as monotherapy and combination therapy with DPP-4 inhibitors for the treatment of NASH.


H. Park: Employee; Self; Dong-A ST Co., Ltd. S. Lee: Employee; Self; Dong-A ST Co., LTD. M. Kim: Employee; Self; Dong-A ST Co., Ltd.

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