KEY ROLE OF KUPFFER CELLS IN THE DEVELOPMENT OF NAFLD INDUCED BY A SUCROSE-RICH DIET

WISZNIEWSKI M; CYMERYNG CB; MORI D; PEZZANITTI A; REPETTO EM

Congreso; V INTERNATIONAL CONGRESS IN TRANSLATIONAL MEDICINE; 2021

Non-Alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease. Although of yet unknown origin, several factors such as oxidative stress and inflammation were postulated to contribute to its etiology. Previous results from our laboratory showed an increase in parameters of oxidative stress, tissue injury, insulin resistance and inflammation in the liver of rats fed a sucrose rich diet (SRD) for 12 weeks Administration of hemin, during the last two weeks of the dietary modification (15mg/kg ip, every 48hs) prevented these alterations. Hemin treatment caused the induction of HO-1 in Kupffer cells, the hepatic macrophages population. Taking these results into consideration and aiming to clarify the role of Kupffer cells in these effects, we administered gadolinium chloride (Gd) (10mg/kg ip every 3 days) for the last 2 weeks of the SRD-treatment. Our results indicate that neither hemin nor Gd could modified caloric intake, corporal weight, or hepatic triglyceride content. Only hemin treatment ameliorated hepatic insulin resistance, assessed by the phosphorylation levels of AKT in Ser473. Hemin treatment also resulted in a significant decrease in serum TAG levels in SRD-treated animals, that was associated with the activation of β-oxidation, via AMPK/PPARα/ACOX1, in the liver. Although Gd had no effect on serum TAG levels in SRD-treated animals it was able to prevent hepatic injury, as assessed by s100a9 expression and H&E staining. Administration of Gd was also accompanied by a decrease in the activity of antioxidant enzymes as SOD and catalase. Based on the results obtained with Gd, we hypothesize that some deleterious effects (e.g. generation of oxidative stress) associated with the administration of SRD could be attributed to the activation of Kupffer cells, as its depletion by Gd exerts a protective effect from diet-induced damage. We also propose that hemin treatment induces a phenotypic change in Kupffer cells that, in addition to the induction of HO-1, also results in the decrease in oxidative stress markers and in the activation of metabolic pathways leading to a decrease in the secretion of TAG from the liver. Present results do not allow us to discard direct effect of hemin in the hepatocytes