RECEPTOR 1 (TNFR1) SIGNALING PATHWAY IN THE PROGRESSION OF HEPATIC STEATOSIS AND LIVER DAMAGE

DANIEL E. FRANCÉS; EDUARDO A. ROGGERO; AINELÉN S. ARBOATTI; CRISTINA E. CARNOVALE.; GERARDO B. PISANI; FLAVIA LAMBERTUCCI ; MARÍA T. RONCO; ARIEL D. QUIROGA; JUAN A. MONTI

Buenos Aires

Congreso; Sociedad argentina de Investigaciones Clínicas (SAIC) y SAFIS; 2017

SAIC y SAFIS

In obese individuals, the excess fat accumulates inthe liver and it is associated with hepatic low grade inflammation.Pro-inflammatory cytokines as TNF-a, IL-6 or IL-1β promote sustainedinflammation that increase the susceptibility of hepatocytes toapoptotic cell death and therefore exacerbate liver damage. Weevaluated the effects of high caloric feeding on the phenotype ofTNFR1 knockout mice to assess its role in the progression ofsteatohepatitis, apoptosis and liver damage. C57BL/6J wild type (WT)and knockout C57BL/6-Tnfrsf1atm1Imx/J (TNFR1 KO) mice (n=6) werefed with regular chow diet (CHOW) or a 40% high-fat diet(HFD) for 16 weeks. Liver pro-inflammatory cytokines mRNA wasincrease in HFD-KO compared with HFD-WT (RT-PCR; IL-1β: 6-foldincrease; TNFa: 2-fold increase; IL-6: 4-fold increase),but only plasmatic IL-1β levels showed a statistically significantincrease in HFD-KO mice (ELISA; HFD-WT: 189 pg/ml; HFD-KO: 1078 pg/ml).In line with this, liver immunoblot membrane expression of itsreceptor was increased in HFD-KO (+40%) vs HFD-WT (p<0.05).Histological sections showed moderate to severe lobularinflammation and lipid accumulation with clear fat vacuoles involving zone 3in the liver of HFD-KO mice (H&E staining) compared with mildinflammation and lipid accumulation in HFD-WT mice. Additionally,hepatic triglyceride content was higher in HFD-KO livers (colorimetricassay;+46% vs HFD-WT; p<0.05). In this regard, HFD-KO mice showedan increase of hepatic damage assessed by: plasmatic alanineaminotransferase (ALT) activity (+25%; p<0.05). In addition,apoptotic process was higher in HFD-KO livers [Caspase-3 fluorescenceactivity (u.a.): HFD-WT: 2039±495; HFD-KO: 35000±17100 (p<0.05) andApoptotic index (+143%; p<0.05)]. Based on these results, wesuggest that the disruption of TNFR1 signaling pathway increasesinterleukin-1β levels, liver inflammation and promotes theprogression to steatohepatitis exacerbating HFD-derived liver damage.