HO-1 AS A THERAPEUTIC TARGET IN A RAT MODEL OF MAFLD: KEY ROLE OF KUPFFER CELLS

MORI D; WISZNIEWSKI M; CYMERYNG CB; REPETTO EM; MARTINEZ CALEJMAN C

Congreso; Reunión Anual de Biociencias 2021; 2021

Currently, metabolic dysfunction associated with fatty liver affects a quarter of the world population, but no pharmacological treatment has been recommended yet. We have previously shown that depletion of Kupffer cells (KC) in rats fed a sucrose-rich diet (SRD) for 12 weeks attenuates tissue injury and prevents liver inflammation, without changing the degree of steatosis. The aim of this study was to evaluate the effects of hemin treatment (an HO-1 inducer) on liver damage induced by SRD and identify the underlying mechanisms.SRD-treated rats are presented with IR, hepatic steatosis, and high serum levels of NEFAS, glycemia, and triacylglycerides (TAG). Administration of hemin for the last two weeks of the dietary intervention (15 mg/kg/48h, SRD+H) did not modify these parameters, except for the observed reduction in serum TAG levels. A lower degree of ballooning (histological change compatible with injury) as well as a decrease in oxidative stress parameters (TBARS and 3-nitrotyrosine levels, SOD and catalase activities), UPR (expression of XBP1s, ATF4 and GRP78) and apoptosis (TUNEL and cleaved caspase-3 expression) were also detected in SRD-treated rats. The induction of HO-1 expression in KC by hemin was associated with lower tissue levels of IL1, TNF and pP65 compared to the SRD group. Induction of PEPCK as well as the response to pyruvate were blocked by hemin, that also restored the ratio pAkt/Akt altered by SRD. Finally, animals in the SRD+H group showed an increase in the expression of PPAR, CPT1 and ACOX1 (proteins involved in lipid oxidation), and an increase in pAMPK (vs. SRD). In summary, our results lead us to hypothesize that administration of hemin attenuates liver injury induced by sucrose diet by reducing the pro-inflammatory tone of the KC associated with the induction of HO-1. Moreover, hemin treatment is also able to decrease TAG serum levels by increasing lipid oxidation through the stimulation of the AMPK/PPAR pathway in the liver.