1604-P: DPP-4 Inhibitor and SGLT2 Inhibitor Additively Ameliorate Hepatic Steatosis in NAFLD Model Mice through Different Action Mechanisms
Authors: IWAMOTO YUICHIRO , KIMURA TOMOHIKO , IWAMOTO HIDEYUKI , FUSHIMI YOSHIRO , SANADA JUNPEI , KATAKURA YUKINO , SHIMODA MASASHI , MUNE TOMOATSU , KAKU KOHEI , KANETO HIDEAKI 
Published: June 2023

Nonalcoholic fatty liver disease (NAFLD) is closely associated with the development and pathogenesis of type 2 diabetes mellitus (T2DM). Luseogliflozin (Luseo) has been reported to improve NAFLD in T2DM model mice by affecting factors related to fatty acid synthesis and beta oxidation. Anagliptin (Ana) improves NAFLD in mice by altering the M1/M2 macrophage ratio. The aim of this study is to assess the molecular mechanisms of DPP4 and SGLT2 inhibitors, which are often used in combination clinically, on NAFLD. Six-week-old male C57BL/6J mice were fed a high fat diet (HFD) to create a diet-induced NAFLD model, and at 14 weeks of age, the mice were divided into 4 groups: control, Luseo (15 mg/kg/day: mixed diet), Ana (300 mg/kg/day: mixed water), and combination group. After the 4 weeks intervention, various metabolic parameters were evaluated. In addition, the expression of mRNAs was analyzed by qPCR. Luseo and combination groups showed a significant reduction in body weight. HE and Oil-Red-O staining demonstrated an improvement of hepatocyte ballooning and decreased fat staining area in the combination compared to the control. Liver qPCR showed that the expression levels of genes related to lipid synthesis and glycogenesis such as SCD1 and PEPCK in Luseo were decreased and inflammatory response such as IL6 were decreased in Ana. The expression levels of chemokine-related genes including CCL3, CCL4, and CCL5 were also decreased in Ana. Those findings observed in Luseo and Ana groups were also confirmed in the combination. In summary, Luseo improved lipid synthesis and glycogenesis in addition to body weight reduction, and reduced inflammation-related factors, while Ana suppressed inflammatory cytokines and chemokine-related pathways. Combination of two drugs markedly ameliorated hepatocyte fat deposition. Thus, it is likely that both DPP-4 inhibitor and SGLT2 inhibitor contributed to the improvement of NAFLD through different action mechanisms.

Disclosure
Y. Iwamoto: Speaker's Bureau; Kowa Company, Ltd. T. Kimura: Speaker's Bureau; Sanwa Kagaku Kenkyusho, Kowa Research Institute, Inc., Taisho Pharmaceutical Holdings Co., Ltd., Boehringer Ingelheim Japan, Inc., Sumitomo Dainippon Pharma Co., Ltd., Sanofi, MSD Life Science Foundation, Lilly, Daiichi Sankyo, Novo Nordisk. H. Iwamoto: None. Y. Fushimi: None. J. Sanada: Speaker's Bureau; Lilly, Kowa Company, Ltd. Y. Katakura: Speaker's Bureau; Abbott. M. Shimoda: Speaker's Bureau; Sanofi, Lilly, AstraZeneca, Ono Pharmaceutical Co., Ltd., Kowa Company, Ltd., Novo Nordisk, Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd., MSD Life Science Foundation, Mitsubishi Tanabe Pharma Corporation. T. Mune: None. K. Kaku: Speaker's Bureau; Astellas Pharma Inc., Daiichi Sankyo, Eli Lilly Japan K.K., Boehringer Ingelheim Japan, Inc., Kowa Company, Ltd., Mitsubishi Tanabe Pharma Corporation. Advisory Panel; Novo Nordisk. Consultant; Sanwa Kagaku Kenkyusho. Speaker's Bureau; Taiho Pharmaceutical Co. Ltd., Takeda Pharmaceutical Co., Ltd. H. Kaneto: Research Support; Sumitomo Dainippon Pharma Co., Ltd., Taiho Pharmaceutical Co. Ltd., Boehringer Ingelheim Japan, Inc. Speaker's Bureau; Lilly, Sanofi, Boehringer Ingelheim Japan, Inc., Novo Nordisk, Sumitomo Dainippon Pharma Co., Ltd. Research Support; Abbott.