Abstract
Empagliflozin, an established treatment for type 2 diabetes (T2DM), has shown beneficial effects on liver steatosis and fibrosis in animals and in humans with T2DM, non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH). However, little is known about the effects of empagliflozin on liver function in advanced NASH with liver fibrosis and without diabetes. This study aimed to assess the effects of empagliflozin on hepatic and metabolic outcomes in a diet-induced obese (DIO) and insulin-resistant but non-diabetic biopsy-confirmed mouse model of advanced NASH. Male C57BL/6JRj mice with a biopsy-confirmed steatosis and fibrosis on AMLN diet (high fat, fructose and cholesterol) for 36-weeks were randomized to receive for 12 weeks: (a) Empagliflozin (10 mg/kg/d p.o.), or (b) vehicle. Metabolic outcomes, liver pathology, markers of Kupffer and stellate cell activation and lipidomics were assessed at the treatment completion. Empagliflozin did not affect the body weight, body composition or insulin sensitivity (assessed by intraperitoneal insulin tolerance test), but significantly improved glucose homeostasis as assessed by oral glucose tolerance test in DIO-NASH mice. Empagliflozin improved modestly the NAFLD activity score compared with the vehicle, mainly by improving inflammation and without affecting steatosis, the fibrosis stage and markers of Kupffer and stellate cell activation. Empagliflozin reduced the hepatic concentrations of pro-inflammatory lactosylceramides and increased the concentrations of anti-inflammatory polyunsaturated triglycerides. Empagliflozin exerts beneficial metabolic and hepatic (mainly anti-inflammatory) effects in non-diabetic DIO-NASH mice and thus may be effective against NASH even in non-diabetic conditions.
Highlights
Introduction published maps and institutional affilNon-alcoholic fatty liver disease (NAFLD) is a metabolic disease with a continuously increasing prevalence that is currently affecting approximately 30% of the general population and 40–50% of patients with type 2 diabetes (T2DM) and obesity [1,2]
Empagliflozin Has No Major Effect on Body Weight or Body Composition in diet-induced obese (DIO)-NASH Mice. Both DIO-NASH mice treated with a vehicle as well as DIO-NASH mice treated with empagliflozin gained approximately 5% body weight during the 12 weeks of treatment whereas mice fed a chow diet gained significantly less weight (Figure 1)
Empagliflozin Improves Glucose Homeostasis Without Affecting Insulin Sensitivity in DIO-NASH mice treated with a vehicle had slightly higher fasting glucose levels at the treatment start and a similar response in the oral glucose tolerance test (OGTT) at week 7 compared with the chow mice suggesting the presence of a mild hyperglycemia but no overt diabetes (Figure 2)
Summary
Non-alcoholic fatty liver disease (NAFLD) is a metabolic disease with a continuously increasing prevalence that is currently affecting approximately 30% of the general population and 40–50% of patients with type 2 diabetes (T2DM) and obesity [1,2]. NAFLD is characterized by an increased intrahepatic lipid accumulation (non-alcoholic fatty liver, NAFL) [1,2]. Hepatic inflammation occurs (nonalcoholic steatohepatitis, NASH) and can lead to liver fibrosis and cirrhosis. Despite the high prevalence of NASH, no specific treatment for the disease exists to date [1,2,3]. Due to the strong pathophysiological links between obesity, insulin resistance, diabetes and the development progression of NASH, many studies have focused on the investigation of already licensed anti-diabetic medications for the treatment of NASH [1,2,3,4].
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