CONICET | Buscador de Institutos y Recursos Humanos

Since the induction of oxidative stress and endoplasmic reticulum stress have been both related to the generation of inflammation, characteristic of the progression of NAFLD (non-alcoholic fatty liver disease) the goal of the present study was to evaluate the effects of HO-1 induction in the liver of insulin resistant (IR) animals. Male Wistar rats were assigned to control or SRD groups (30% sucrose in the drinking water). Hemin (15 mg/kg/48h, i.p.) was administered during the last two weeks of treatment (H and SRD+H).Hemin treatment did not modify biochemical systemic parameters. However, HO-1 induction attenuated the SRD-dependent increases in lipoperoxide levels (TBARS), in the activities of antioxidant enzymes (catalase and SOD) and in the number of apoptotic cells assessed by TUNEL or cleaved-caspase 3 by western blot. In addition hemin also normalized serum ALT activity (marker of liver damage). Hemin treatment had no effect on the increases in ED1+ cells (phagocytic cells) or IBA1+ cells (monocyte-derived) induced by diet. Analysis of unfolded protein response (UPR)-related transcription factors showed an increase in the levels of XBP1s, ATF4 and ATF6 in the nuclear fraction of livers from SRD-rats. Hemin treatment blocked the increases of XBP1s and ATF4. Liver induction of HO-1 was confirmed by WB. Confocal microscopy showed the co-localization of HO-1+ and Iba1+ and of ED1+ and CLEC4f+ (Kupffer cells) in the liver of hemin-treated rats. In conclusion, HO-1 induction, mainly in inflammatory cells, decreases oxidative stress, blocked UPR induction and inhibits apoptosis in IR rats. We thus hypothesize a role for oxidative stress in the induction of ER stress and apoptosis in inflammatory cells of the liver, and the involvement of these processes in the progression of NAFLD in SRD-treated rats.