J Nutr Biochem. 2018 May 02. pii: S0955-2863(18)30043-3. [Epub ahead of print]58 17-27
Flavia Lambertucci,
Ainelén Arboatti,
María Guillermina Sedlmeier,
Omar Motiño,
María de Luján Alvarez,
María Paula Ceballos,
Silvina R Villar,
Eduardo Roggero,
Juan A Monti,
Gerardo Pisani,
Ariel D Quiroga,
Paloma Martín-Sanz,
Cristina Ester Carnovale,
Daniel Eleazar Francés,
María Teresa Ronco.
Obesity is accompanied by a low-grade inflammation state, characterized by increased proinflammatory cytokines levels such as tumor necrosis factor alpha (TNFα) and interleukin-1 beta (IL-1β). In this regard, there exists a lack of studies in hepatic tissue about the role of TNFα receptor 1 (TNFR1) in the context of obesity and insulin resistance during the progression of nonalcoholic fatty liver disease (NAFLD). The aim of this work was to evaluate the effects of high-caloric feeding (HFD) (40% fat, for 16 weeks) on liver inflammation-induced apoptosis, insulin resistance, hepatic lipid accumulation and its progression toward nonalcoholic steatohepatitis (NASH) in TNFR1 knock-out and wild-type mice. Mechanisms involved in HFD-derived IL-1β release and impairment of insulin signaling are still unknown, so we determined whether IL-1β affects liver insulin sensitivity and apoptosis through TNFα receptor 1 (TNFR1)-dependent pathways. We showed that knocking out TNFR1 induces an enhanced IL-1β plasmatic release upon HFD feed. This was correlated with higher hepatic and epididymal white adipose tissue mRNA levels. In vivo and in vitro assays confirmed an impairment in hepatic insulin signaling, in part due to IL-1β-induced decrease of AKT activation and diminution of IRS1 levels, followed by an increase in inflammation, macrophage (resident and recruited) accumulation, hepatocyte apoptotic process and finally hepatic damage. In addition, TNFR1 KO mice displayed higher levels of pro-fibrogenic markers. TNFR1 signaling disruption upon an HFD leads to an accelerated progression from simple steatosis to a more severe phenotype with many NASH features, pointing out a key role of TNFR1 in NAFLD progression.
Keywords: High-fat diet; IL-1 beta; IRS1; Inflammation; Insulin resistance; Nonalcoholic liver disease; TNFR1