Inhibition of sodium glucose cotransporter 2 (SGLT2) delays liver fibrosis in a medaka model of nonalcoholic steatohepatitis (NASH)

Abstract

The rise in the incidence of nonalcoholic steatohepatitis (NASH) has necessitated the development of an effective prevention methodology. An antidiabetic drug, belonging to the group of sodium glucose cotransporter 2 (SGLT2) inhibitors, has been tested for its therapeutic effect on NASH; however, no studies to date have demonstrated the preventive effect of an SGLT2 inhibitor on the histological progression of steatosis and fibrosis in a sequential manner in animal models. In the present study, we examined the effect of the SGLT2 inhibitor, tofogliflozin (Tofo), on NASH liver tissue using medaka as an animal model, maintaining a feeding amount and drug concentration in all animal bodies. We generated a medaka NASH model by feeding d‐rR/Tokyo medaka a high‐fat diet and administered Tofo by dissolving the drug directly in the water of the feeding tank. Thereafter, the effects of Tofo on body weight (BW), liver weight, hepatotoxicity, fatty infiltration, and fibrotic changes in the liver were examined. We report here that SGLT2 is expressed in medaka fish and that Tofo inhibits the accumulation of fatty tissue and delays the progression of liver fibrosis in the medaka NASH model by inhibiting increases in blood sugar, serum lipids, and transaminase, irrespective of changes in BW. These results suggest that Tofo is effective for treating NASH and that the medaka model may be useful for developing new therapeutic drugs for this disease.

Inhibition of sodium‐glucose cotransporter 2 ameliorates renal injury in a novel medaka model of nonalcoholic steatohepatitis‐related kidney disease

“…1B) and that Tofo ameliorates the changes (Fig. 1C) as previously reported [25]. The HFD group exhibited enlargement of the renal size from the control level of 737.7 AE 101.3 µm to 1645.5 AE 109.8 µm following 12 weeks of HFD feeding, whereas the HFD + Tofo group showed milder enlargement to 1343.3 AE 92.…”

Atorvastatin promotes AMPK signaling to protect against high fat diet‑induced non‑alcoholic fatty liver in golden hamsters

“…Animal models of NAFLD induced by HFD (32,33) have been widely used to examine the pathogenesis of NAFLD and to investigate new treatment strategies (34). HFD-induced liver disease, in contrast with rifampicin-isoniazid-induced hepatotoxicity (35), not only leads to chronic inflammation and liver fibrosis, but also disrupts endoplasmic reticulum calcium homeostasis (36)(37)(38).…”

Pathophysiological Mechanisms in Non-Alcoholic Fatty Liver Disease: From Drivers to Targets

“…These compounds boost renal excretion of glucose by lowering kidney reabsorption, ultimately resulting in reduced circulating levels of glucose, and inhibition of both ChREBP and SREBP-1c activity [ 205 , 247 ]. As recently described, several studies report beneficial effects of SGLT2i in NASH in vivo models, such as attenuation of hepatic steatosis, inflammation, and fibrosis, as well as prevention of both NASH and NASH-related HCC development [ 248 , 249 , 250 , 251 ]. Regarding human clinical trials, only few relatively small studies have been conducted with SGLT2i in NAFLD/NASH patients, making it difficult to draw robust conclusions.…”