Efeitos anti-esteatóticos da linagliptina na supressão da lipogênese de novo e do estresse do retículo endoplasmático em camundongos alimentados com dieta hiperlipídica

Abstract

The paper aims to investigate the effects of linagliptin treatment on hepatic energy metabolism and endoplasmic reticulum stress in C57BL / 6 mice fed a high fat diet. Forty 3-month-old male C57BL / 6 mice received either a control diet (C, 10% lipid as energy, n = 20) or a hyperlipid diet (HF, 50% lipid as energy, n = 20) for 10 weeks. Subsequently, the groups were randomly divided into four groups to receive linagliptin (L) for 5 weeks at a dose of 30mg / kg / day added to the diets: groups C, C-L, HF and HF-L. Biochemical analyzes, stereology, qPCR for genes related to beta oxidation, lipogenesis and stress of the endoplasmic reticulum were performed. The HF group showed increased body mass, total and hepatic cholesterol levels and total and hepatic triacylglycerol levels compared to group C, which were significantly reduced by linagliptin in the HF-L group. Group HF had higher hepatic steatosis than group C, while linagliptin markedly reduced hepatic steatosis (-52%, P <0.001). The expression of Sirt1 and Pgc1a was higher in the HF-L group than in the HF group. Linagliptin also caused a reduction in lipogenic gene expression Fas and Srebp1c. In addition, HF-L showed a reduction in stress-related genes of the endoplasmic reticulum Chop, Atf4 and Gadd45, associated with reduced immunostaining of apoptotic nuclei. Linagliptin caused marked reduction in hepatic steatosis based on suppression of lipogenic genes and induction of beta-oxidation genes. This pattern of gene expression caused stress relief in the endoplasmic reticulum, leading to reduced apoptosis and better preservation of liver structure. Therefore, linagliptin may preferably be used in diabetic patients to prevent the progression of hepatic steatosis.