Disruption of tumour necrosis factor-alpha receptor 1 signalling pathway increases interleukin-1 beta levels, exacerbates liver insulin resistance and apoptosis during a high fat diet

LAMBERTUCCI, FLAVIA; ROGGERO, EDUARDO; FRANCÉS, DANIEL ELEAZAR; SEDLMEIER, MARÍA G; CARNOVALE, CRISTINA ESTER; ARBOATTI, AINELÉN; QUIROGA, ARIEL DARÍO; RONCO, MARÍA TERESA

Amsterdam

Congreso; 52nd annual EASL meeting. The International Liver Congress? 2017; 2017

THE EUROPEAN ASSOCIATION FOR THE STUDY OF THE LIVER

Background and Aims: Obesity-associated hepatic sustained inflammation may increase the susceptibility of hepatocytes to apoptotic cell death and therefore exacerbate liver damage. Chemokines, as TNF-alpha and interleukin (IL) 1-beta, play pivotal roles in the recruitment of immune cells at sites of inflammation and in the development of insulin resistance. Given the lack of studies in hepatic tissues about the role of TNFR1 in the context of obesity and insulin resistance, the aim of this study was to determine if TNFR1-dependent pathways affects insulin sensitivity through increased levels of IL-1beta and its association with liver inflammation induced-apoptosis.Methods: C57BL/6J wild type (WT) and knockout C57BL/6-Tnfrsf1atm1Imx/J (KO) mice (n=6) were fed with regular chow diet (CHOW) or a 40% high-fat diet (HFD) for 16 weeks. For hepatic insulin signaling studies mice were intra peritoneal injected with insulin (0.75 U/kg) 15 min before sacrifice. Liver was removed for histological analysis, caspase 3 activity assay and Western Blot. Plasma determinations were realized by ELISA. For in vitro studies, cells were isolated by perfusion with collagenase and analyzed by flow cytometry or cultured for Western Blot assay.Results: TNFR1 KO mice showed reduced body mass gain, adipose tissue and had lower plasma insulin levels. Plasma IL-1beta levels (HFD-WT=189 pg/ml; HFD-KO=1078 pg/ml) and hepatic membrane expression of its receptor (+40%) were increased in HFD-KO (p