CONICET | Buscador de Institutos y Recursos Humanos

Since the induction of oxidative stress and endoplasmic reticulum stress have been bothrelated 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 ofHO-1 induction in the liver of insulin resistant (IR) animals. Male Wistar rats were assignedto 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 treatmentdid not modify biochemical systemic parameters. However, HO-1 induction attenuated theSRD-dependent increases in lipoperoxide levels (TBARS), in the activities of antioxidantenzymes (catalase and SOD) and in the number of apoptotic cells assessed by TUNEL orcleaved-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 unfoldedprotein response (UPR)-related transcription factors showed an increase in the levels ofXBP1s, ATF4 and ATF6 in the nuclear fraction of livers from SRD-rats. Hemin treatmentblocked 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 + andCLEC4f + (Kupffer cells) in the liver of hemin-treated rats. In conclusion, HO-1 induction,mainly in inflammatory cells, decreases oxidative stress, blocked UPR induction andinhibits apoptosis in IR rats. We thus hypothesize a role for oxidative stress in theinduction of ER stress and apoptosis in inflammatory cells of the liver, and the involvementof these processes in the progression of NAFLD in SRD-treated rats