Delayed intervention with a novel SGLT2 inhibitor NGI001 suppresses diet‐induced metabolic dysfunction and non‐alcoholic fatty liver disease in mice

Abstract

Background and Purpose: Non-alcoholic fatty liver disease (NAFLD), including non-alcoholic steatohepatitis, 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: Inhibition of the sodium-glucose cotransporter 2 (SGLT2) 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, hyperglycaemia, hyperlipidaemia, and hyperinsulinaemia, 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 but had little effect on kidney function.In-depth investigations showed that NGI001 ameliorated fat deposition and increased AMPK phosphorylation, resulting in phosphorylation of its major downstream target, acetyl-CoA carboxylase, in human hepatocyte HuS-E/2 cells. This cascade ultimately led to the down-regulation of downstream fatty acid synthesisrelated molecules and the up-regulation of downstream β 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 novel SGLT2 inhibitor, NGI001 has therapeutic potential to attenuate or delay the onset of diet-induced metabolic diseases and NAFLD.

Adlay Seed (Coix lacryma-jobi L.) Extracts Exhibit a Prophylactic Effect on Diet-Induced Metabolic Dysfunction and Nonalcoholic Fatty Liver Disease in Mice

“…e analysis of blood glucose, serum insulin, intraperitoneal glucose tolerance test, and the homeostasis model assessment of insulin resistance index were performed as described previously [19].…”

“…For hepatic triglyceride and cholesterol determinations, the methods were performed as described previously [19].…”

“…e horseradish peroxidase-conjugated anti-mouse or anti-rabbit IgG antibodies were from Abcam. Western blot analysis was performed as previously described [19].…”

Effects of Sodium-Glucose Cotransporter 2 Inhibitors on Hepatic Fibrosis in Patients With Type 2 Diabetes: A Chart-Based Analysis

“…SGLT2is could activate adenosine 5'-monophosphate-activat- Katsuyama et al J Endocrinol Metab. 2020;10(1):1-7 ed protein kinase (AMPK) by inhibiting mitochondrial function and elevating adiponectin levels [16,20], leading to upregulation of fatty acid (FA) oxidation in skeletal muscle and liver as well as downregulation of FA synthesis in the liver [21,22]. The decrease of fat accumulation reduces oxidative stress and inflammation [8].…”

The analysis of a wide spectrum of activity of Sodium-Glucose co-transporter-2 inhibitors. A literature review

“…The decrease in the deposition and synthesis of fatty acids was most probably related to the reduced activity of acetyl-CoA carboxylase. Moreover, gliflozin improved the regulation of carbohydrate metabolism and decreased insulin resistance [22].…”