Hemin treatment reverts liver injury due to the chronic consumption of a sucrose rich diet

WISZNIEWSKI, MORENA; VECINO, CAROLINA V; CALDARERI L; SANCHEZ PUCH, S; CYMERYNG, CB; REPETTO, EM

CABA

Congreso; 4th INTERNATIONAL CONGRESS IN TRANSLATIONAL MEDICINE; 2018

FFYB-UBA

Non-alcoholic fattyliver disease (NAFLD) is the most common chronic liver disease, representingthe hepatic component of metabolic syndrome. It comprises a wide spectrum ofhistological alterations, from simple steatosis to non-alcoholicsteatohepatitis. Since the long-term consumption of sucrose rich diets (SRD)has been shown to induce damage to hepatic tissue attributed to the generationof oxidative stress, our main objective was to evaluate the effects of systemichemin treatment, known to induce cytoprotective HO-1 activity, on hepaticparameters of insulin resistant (IR) animals. For this purpose, male Wistarrats were randomly distributed into control (C) or SRD groups (30% sucrose inthe drinking water over 12 weeks). Hemin (15 mg/kg/48h, ip) was administeredduring the last two weeks of treatment (H and SRD+H groups). Our resultsindicate that, compared to controls,  rats fed a SRD present higher levels ofglycaemia and triglyceridemia. Neither glycaemia nor the TG/HDLc index or PEPCKprotein levels (assessed by western blot) were modified by hemin treatment, suggestingthat this treatment does not affect the IR state of the animals. Nevertheless,  hemin administration attenuated the increasesin lipoperoxide levels (TBARS), in the activities of antioxidant enzymes (suchas catalase and SOD) and in apoptosis, assessed by the number of TUNEL positivecells, and the measurement of cleaved caspase-3 levels by western blot. Thistreatment also normalized the serum activity of alanine transaminase (ALT), amarker of liver damage that was augmented in the SRD group (p<0,05 vs. SRD).Immunohistochemical analysis of hepatic tissues showed an increased expressionof ED1 (marker of phagocytic activity)in both SRD groups (SRD and SRD+H)  while no significant changes in Iba1, amonocyte-derived cell marker (by immunofluorescence) or F4/80 (by western blot)between groups. We also demonstrated the co-localization of ED1 with CLEC4f,  a specific marker for Kupffer Cells (KC) byconfocal microscopy. HO-1 induction by hemin treatment was confirmed in theliver by western blot and confocal microscopy, where the signal wasco-localized with IBA-1, indicating that HO-1 is induced in inflammatory cells.In conclusion, long term consumption of a sucrose rich diet causes an increasedaccumulation of lipids in the liver (hepatic steatosis) and generates oxidativestress (OS), tissue inflammation and also cell death (apoptosis). Treatmentwith hemin induces HO-1 expression mainly in Kupffer cells,and significantly attenuates these effects of diet on the liver. As theseresident macrophage cells are the main producers of cytokines we hypothesizethat HO-1 induction, due to its antioxidant effect, attenuates inflammation,and hence prevents the progression of the hepatic disease.