CD4+RORγt++ and Tregs in a Mouse Model of Diet‐Induced Nonalcoholic Steatohepatitis

Abstract

Background and Aims. Inflammatory mediators that cross-talk in different metabolically active organs are thought to play a crucial role in the pathogenesis of Nonalcoholic Steatohepatitis (NASH). This study was aimed at investigating the CD4+RORγt+ T-helper cells and their counterpart, the CD4+CD25+FOXP3+ regulatory T cells in the liver, subcutaneous adipose tissue (SAT), and abdominal adipose tissue (AAT) in a high fat diet (HFD) mouse model. Methods. C57BL6 mice were fed a HFD or a normal diet (ND). Liver enzymes, metabolic parameters, and liver histology were assessed. The expression of CD4+RORγt+ cells and regulatory T cells in different organs (blood, liver, AAT, and SAT) were analyzed by flow cytometry. Cytokine and adipokine tissue expression were studied by RT-PCR. Results. Mice fed a HFD developed NASH and metabolic alterations compared to normal diet. CD4+RORγt++ cells were significantly increased in the liver and the AAT while an increase of regulatory T cells was observed in the SAT of mice fed HFD compared to ND. Inflammatory cytokines were also upregulated. Conclusions. CD4+RORγt++ cells and regulatory T cells are altered in NASH with a site-specific pattern and correlate with the severity of the disease. These site-specific differences are associated with increased cytokine expression.

Animal Models of Nonalcoholic Fatty Liver Disease—A Starter’s Guide

“…ALT and AST levels are significantly increased after 34–36 weeks. However, this diet induces only minimal fibrosis after extended exposure (36–50 weeks) [ 46 , 47 ]. As was mentioned above, it should be noted that the time of onset and degree of both the metabolic features and NAFLD is dependent of species, strain, sex and composition of gut microbiota, as well as dietary fat content.…”

Immune Imbalances in Non-Alcoholic Fatty Liver Disease: From General Biomarkers and Neutrophils to Interleukin-17 Axis Activation and New Therapeutic Targets

“…In another study using mice fed with high-fat diet (HFD), there was a significant increase of Th17 cells in the liver ( P  < 0.02) and the abdominal adipose tissue (AAT) ( P  < 0.01), without a concurrent increase of Treg (60). NASH and metabolic alterations occurred in mice-fed HFD, and Th17 cells (either AAT or liver-derived) positively correlated with NASH (60).…”

“…In another study using mice fed with high-fat diet (HFD), there was a significant increase of Th17 cells in the liver ( P  < 0.02) and the abdominal adipose tissue (AAT) ( P  < 0.01), without a concurrent increase of Treg (60). NASH and metabolic alterations occurred in mice-fed HFD, and Th17 cells (either AAT or liver-derived) positively correlated with NASH (60). Other studies have shown in parallel that the reduction, dysfunction, or disproportionate number of Treg cells contributes to the progression to NASH because Treg cells play a critical role in regulating the inflammatory processes in the liver (24, 29, 30).…”

NAFLD Preclinical Models: More than a Handful, Less of a Concern?

“…Despite hepatic steatosis, inflammatory cell infiltration was not present until 19 weeks of HFD intake [19]. While after long-term (34-36 weeks) HFD feeding, significant increases in circulating liver enzyme levels, i.e., alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were observed [19], these mice showed only minor signs of inflammation and fibrosis [21], even after prolonged administration up to 50 weeks [19]. Yet, after chronic feeding (80 weeks) of HFD, which mimics lifetime HFD consumption and enables proper design of treatment options, Velázquez et al [17] demonstrated that mice displayed obesity and insulin resistance.…”