GPR119 activation is known to inhibit de novo lipogenesis in hepatocytes, but it still remains elusive if and how GPR119 agonists can affect the pathogenesis of hepatic inflammation and fibrosis in NASH. Herein, we report the therapeutic potential of DA-1241 for NASH, especially for hepatic inflammation and fibrosis. DA-1241 was given to ob/ob mice with western diet for 10 weeks. Plasma and liver tissue samples were tested for biochemical and histological analyses. Human monocyte cells and primary hepatic stellate cells were used for in vitro proof-of-concept. At the end of experiment, ob/ob NASH mice distinctly exhibited increased plasma total cholesterol and hepatic lipid accumulation, but plasma glucose and triglyceride values were within normal range. After 10-weeks of treatment, DA-1241 significantly blocked the progression of hepatic inflammation and fibrosis compared to the NASH control (-39% and -64% for NAS and fibrosis score; p<0.05), while MBX-2982, a GPR119 agonist under clinical development, failed to reach statistical significance at the same dose (-19.4% and -29%; p>0.05). Moreover, plasma total glucagon-like peptide-1 levels were increased by DA-1241 treatment, but not by MBX-2982. Plasma ALT and AST levels were significantly lower in DA-1241-treated mice, which were much lower than those of MBX-2982-treated mice. Of note, DA-1241 were more efficacious than MBX-2982 in reducing the hepatic expression of fibrotic proteins such as type 1 collagen, α-SMA, and TIMP1, and pro-inflammatory proteins including CCL2, TNFα. To explore its underlying modes of action in vitro, THP-1 macrophages or primary hepatic stellate cells were activated by LPS or TGFβ, respectively. DA-1241 inhibited the differentiation and activation of macrophages and blocked stellate cells activation. Our findings suggest that DA-1241 has a therapeutic potential for NASH, which may be partly attributed to blocking macrophage and stellate cell activation in addition to the inhibition of lipogenesis.
H. Park: Employee; Self; Dong-A ST Co., Ltd. B. Lee: Employee; Self; DONG-A ST Co,Ltd. Y. Chae: Employee; Self; Dong-A ST Co., LTD. M. Kim: Employee; Self; Dong-A ST Co., Ltd.