Efeitos pleiotrópicos do inibidor SGLT2, empagliflozina, em modelo experimental de esteatose hepática

Abstract

There is no exclusive therapy for non-alcoholic fatty liver disease until the present moment, although some drugs have pleiotropic effects. Recently, a pharmacological class of oral hypoglycemic agents, a selective inhibitor of sodium and glucose cotransporter 2 (SGLT2), has been shown to have cardiovascular and hepatic pleiotropic effects, notably empagliflozin, which promotes glycosuria by inhibiting renal resorption and weight loss. As aims, were evaluate , we evaluated the effects induced with high fat diet in C57Bl/6 mice on body mass and glucose tolerance prior to the treatment period and afterwards, were evaluated the pleiotropic effects of empagliflozin in the liver, through the pathways of lipogenesis, β- oxidation and endoplasmic reticulum stress. For this, C57BL/6 male mice (3 months-old) received a control diet (C, 10% lipids, n = 20) or a rich saturated fat diet (HL, 50% lipids, n=20) for 10 weeks. After this period, the groups were subdivided to receive empagliflozin treatment (N=10 per group), for 5 weeks at a dose of 10 mg/kg/day, added the respective diets, in total 4 experimental groups: C, C-EMPA, HL and HL-EMPA. Biochemical analyzes, oral glucose tolerance test, insulin sensitivity, indirect calorimetry, hepatic stereology, immunofluorescence, RT-qPCR for the genes related to β-oxidation, lipogenesis and endoplasmic reticulum stress were performed. In the pre-treatment period, used to induce metabolic alterations, it was observed in the HL group an increase in body mass +11% (BM), hyperglycemia and glucose intolerance +25%, 164% of hepatic steatosis, compared to C group. In contrast, after treatment with empagliflozin, there was an increase of +4% in energy expenditure, with a consequent reduction of -5% in BM, improvement in both glucose tolerance and insulin sensitivity, all compared to the untreated HL group. As regards the expression of PPARα, related to β-oxidation, there was a greater expression in the HL-EMPA group, at the same time as reduction in the expression of the lipogenic genes (FAS, SREBP-1c and PPARγ). In addition, the HL-EMPA group showed a significant reduction in the expression of genes related to endoplasmic reticulum stress (CHOP, ATF4 and GADD45). Our results indicate that empagliflozin reduced body mass, favoring a insulin sensitivity improved and a potential reduction of hepatic steatosis, which is consistent with the reduction in the expression of the genes that act in the hepatic lipogenesis, adding the reduction of the genes involved in the endoplasmic reticulum stress. Thus, inhibition of SGLT2 using empagliflozin may be an important tool to prevent progression of hepatic steatosis.