Hemin Treatment Decreases Oxidative Stress, Apoptosis And Endoplasmic Reticulum Stress In The Liver Of Rats Rendered Insulin Resistant By A Sucrose Rich Diet

VECINO C; CYMERYNG CB; WISZNIEWSKI M; REPETTO EM

Chicago, Illinois

Congreso; 100th Annual Meeting of The Endocrine Society; 2018

The Endocrine Society

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease and represents the hepatic component of metabolic syndrome. Since oxidative stress, inflammation and endoplasmic reticulum stress have been related to the pathogenesis of NAFLD, our objective was to evaluate the effects of systemic hemin treatment, known to induce cytoprotective HO-1 activity, on the liver of insulin resistant (IR) animals. Male Wistar rats were randomly distributed into control (C) or sucrose rich diet (SRD) groups (30% sucrose in the drinking water over 12 weeks). Hemin (15 mg/kg/48h,ip) was administered during the last two weeks of treatment (H and SRD+H groups). Our results indicate that rats fed a SRD showed a decrease in HDL-cholesterol levels and increases on glycaemia and triglyceridemia. Neither glycaemia nor the ratio TG/HDL-cholesterol were modified by hemin treatment. Although HO-1 induction by hemin was confirmed in the liver, no significant changes were observed in liver histology (analyzed by H&E). Nevertheless, hemin attenuated the increases in lipoperoxide levels (TBARS), in the activities of antioxidant enzymes (such as catalase and SOD) and in the number of apoptotic cells (TUNEL assay). In addition hemin normalized the serum activity of alanine transaminase (ALT), a marker of liver damage that was augmented in the SRD group. An augmented expression of ED1 (marker of phagocytic activity), was detected in SRD rats (SRD and SRD+H) by immunofluorescence. No significant changes in the levels of Iba1 (by immunofluorescence) or f4/80 (by immunoblot) were detected between groups. 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. In conclusion, hemin treatment reverts oxidative stress, UPR induction and apoptosis observed in the liver of IR rats after a long term administration of a SRD. Based on the antioxidant effects attributed to this treatment we hypothesize that both ER stress and apoptosis could be induced by oxidative stress triggered by the administration of a SRD.