Induction of HO-1 in the liver of insulin-resistant rats attenuates oxidative stress, ER-stress activation and apoptosis

WISZNIEWSKI, M; CALDARERI, LILIAN JULIA; VECINO, CAROLINA V; CYMERYNG, CORA BEATRIZ; REPETTO, EM

Bariloche

Simposio; South American Symposium in Signal and Molecular Medicine (SISTAM 2018); 2018

SISTAM

Since theinduction of oxidative stress and endoplasmic reticulum stress have been bothrelated to the generation of inflammation, characteristic of the progression ofNAFLD (non-alcoholic fatty liver disease) the goal of the present study was toevaluate 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% sucrosein the drinking water). Hemin (15 mg/kg/48h, i.p.) was administered during thelast two weeks of treatment (H and SRD+H).Hemin treatment did not modifybiochemical systemic parameters. However, HO-1 induction attenuated theSRD-dependent increases in lipoperoxide levels (TBARS), in the activities ofantioxidant enzymes (catalase and SOD) and in the number of apoptotic cellsassessed by TUNEL or cleaved-caspase 3 by western blot. In addition hemin also normalizedserum ALT activity (marker of liver damage). Hemin treatment had no effect onthe 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 treatmentblocked the increases of XBP1s and ATF4. Liver induction of HO-1 was confirmedby WB. Confocal microscopy showed the co-localization of HO-1+ and Iba1+and of ED1+ and CLEC4f+ (Kupffer cells) in theliver of hemin-treated rats. In conclusion, HO-1 induction, mainly in inflammatorycells, decreases oxidative stress, blocked UPR induction and inhibits apoptosisin IR rats. We thus hypothesize a role for oxidative stress in the induction ofER stress and apoptosis in inflammatory cells of the liver, and the involvementof these processes in the progression of NAFLD in SRD-treated rats.