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.