| Abstract: | BACKGROUND AND PURPOSE: Nonalcoholic fatty liver disease (NAFLD), including nonalcoholic steatohepatitis (NASH), is closely related to metabolic diseases such as obesity and diabetes. Despite an accumulating number of studies, no pharmacotherapy that targets NAFLD has received general approval for clinical use. EXPERIMENTAL APPROACH: Sodium glucose cotransporter 2 (SGLT2) inhibition is a promising approach to treat diabetes, obesity, and associated metabolic disorders. In this study, we investigated the effect of a novel SGLT2 inhibitor, NGI001, on NAFLD and obesity-associated metabolic symptoms in high fat diet (HFD)-induced obese mice. KEY RESULTS: Delayed intervention with NGI001 protected against body weight gain, hyperglycemia, hyperlipidemia and hyperinsulinemia, compared with HFD alone. Adipocyte hypertrophy was prevented by administering NGI001. NGI001 inhibited impaired glucose metabolism and regulated the secretion of adipokines associated with insulin resistance. In addition, NGI001 supplementation suppressed hepatic lipid accumulation and inflammation, and had little impact on kidney function. In-depth investigations showed NGI001 ameliorated fat deposition and increased AMPK phosphorylation, resulting in phosphorylation of its major downstream target, ACC, in human hepatocytes, HuS-E/2 cells. This cascade ultimately led to the downregulation of downstream fatty acid synthesis-related molecules and the upregulation of downstream beta oxidation-associated molecules. Surprisingly, NGI001 decreased gene and protein expression of SGLT1 and SGLT2 and glucose uptake in oleic acid-treated HuS-E/2 cells. CONCLUSION AND IMPLICATIONS: Our findings suggest the therapeutic potential of the novel SGLT2 inhibitor, NGI001, to attenuate or delay the onset of diet-induced metabolic diseases and NAFLD. |
