期刊
JOURNAL OF NUTRITIONAL BIOCHEMISTRY
卷 58, 期 -, 页码 17-27出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.jnutbio.2018.04.013
关键词
High-fat diet; TNFR1; Nonalcoholic liver disease; IL-1 beta; Insulin resistance; Inflammation; IRS1
资金
- Consejo Nacional de Investigaciones Cientificas y Tecnicas [PIP-CONICET 112201500508]
- MINECO, Spain [SAF2016-75004-R, SAF2015-70270-REDT]
Obesity is accompanied by a low-grade inflammation state, characterized by increased proinflammatory cytokines levels such as tumor necrosis factor alpha (TNF alpha) and interleukin-1 beta (IL-1 beta). In this regard, there exists a lack of studies in hepatic tissue about the role of INF alpha 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-1 beta release and impairment of insulin signaling are still unknown, so we determined whether IL-1 beta affects liver insulin sensitivity and apoptosis through TNF alpha receptor 1 (TNFR1)-dependent pathways. We showed that knocking out TNFR1 induces an enhanced IL-1 beta 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-1 beta-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. (C) 2018 Elsevier Inc. All rights reserved.
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