Disruption of tumor necrosis factor alpha receptor 1 signaling accelerates NAFLD progression in mice upon a high-fat diet

Abstract

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.

Tumor necrosis factor alpha receptor 1 deficiency in hepatocytes does not protect from non-alcoholic steatohepatitis, but attenuates insulin resistance in mice

“…These immune cells might have caused the release of different inflammation mediators, such as IL-1β or IL-6, which in turn resulted in activation of inflammatory pathways in hepatocytes that are independent from TNFR1 activation. This hypothesis is supported by a study that used mice with a whole-body knock out of Tnfr1 and also found increased NASH features[ 30 ]. In this study by Lambertucci et al[ 30 ], Tnfr1 deficiency resulted in increased numbers of both resident ( i.e .…”

“…This hypothesis is supported by a study that used mice with a whole-body knock out of Tnfr1 and also found increased NASH features[ 30 ]. In this study by Lambertucci et al[ 30 ], Tnfr1 deficiency resulted in increased numbers of both resident ( i.e . Kupffer cells) and recruited macrophages into the liver, as well as up-regulation of IL-1β and IL-6 in the liver along with increased release into the plasma.…”

“…This suggests that TNF signaling via TNFR1 is important for the development of steatohepatitis. However, results are conflicting, with other studies showing more hepatic steatosis as well as fibrosis and higher inflammatory markers in mouse livers of high-fat diet-induced NAFLD and dysfunctional TNFR1[ 30 ]. Therefore, the role of TNF and TNFR1 signaling in NAFLD and NASH remains unclear.…”

Role of cytokines in pathogenesis and progression of nonalcoholic steatohepatitis

“…20 This cytokine has a lipogenic and fibrogenic effect, mediated by paracrine mechanism involving the activation of Kupffer cell, secretion of soluble mediators that stimulate Ito cell activation into myofibroblast, which in turn is responsible for synthesizing extracellular matrix components that can be used in diagnosing NASH fibrosis. 30 Activin-A is reported to induce follicle-stimulating hormone or FSH and to regulate the menstrual cycle; however, during the last few years activin-A has been found participate in a number of crucial cellular functions, including regulatory of cell cycle and differentiation, apoptosis, metabolism and homeostasis regulation, tumorigenesis, immune responses, wound healing, and fibrosis. Activin-A belongs to transforming-beta growth factor (TGFβ) cytokine superfamily and is a dimer of two identical β subunits.…”

The long‐term protective effects of neonatal administration of curcumin against nonalcoholic steatohepatitis in high‐fructose‐fed adolescent rats

“…TNF α is a potent proinflammatory cytokine (Lambertucci et al. ) that plays an important role in the development of NAFLD, in particular, NASH (Kakino et al. ).…”