Association of Adipose Tissue Inflammation With Histologic Severity of Nonalcoholic Fatty Liver Disease

Abstract

BACKGROUND & AIMS:The prevalence of nonalcoholic fatty liver disease (NAFLD) has increased with the obesity pandemic. We analyzed the transcriptional profiles of subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT), and phenotypes and functional characteristics of adipocyte tissue macrophages (ATMs), in obese patients undergoing bariatric surgery. METHODS: We collected anthropometric data; plasma samples; and SAT, VAT, and liver tissues from 113 obese patients undergoing bariatric surgery at academic hospitals in Europe (Antwerp and Leuven) and South Africa. Based on clinical and histologic features, patients were assigned to the following groups: obese, NAFLD, nonalcoholic steatohepatitis (NASH), or NASH with fibrosis. Microarray analyses were performed to identify genes expressed differentially among groups. We measured levels of cytokines and chemokines in plasma samples and levels of RNAs in adipose tissues by quantitative reverse-transcription polymerase chain reaction. ATMs were isolated from patients and 13 lean individuals undergoing cholecystectomy (controls), analyzed by flow cytometry, and cultured; immunophenotypes and levels of cytokines and chemokines in supernatants were determined. RESULTS: We observed increased expression of genes that regulate inflammation in adipose tissues from patients with NAFLD and NASH; expression of these genes increased as disease progressed from NAFLD to NASH. We found 111 genes associated with inflammation that were expressed differentially between VAT and SAT. Serum levels of interleukin 8, chemokine (C-C motif) ligand 3, and tumor necrosis factor-a correlated with liver inflammation and NAFLD activity score. We developed 2 models that could be used to determine patients' liver histology based on gene expression in VAT and SAT. Flow cytometry showed increased proportions of CD11cþCD206þ and CCR2þ macrophages in VAT from patients with NASH, and supernatants of cultured macrophages had increased levels of cytokines and chemokines compared with controls. CONCLUSIONS: VAT and SAT from patients with NAFLD and NASH have an increased expression of genes that regulate inflammation, and ATM produce increased levels of inflammatory cytokines, compared with adipose tissues from controls. We identified an expression profile of 5 genes in SAT that accurately predict liver histology in these patients. Transcript profiling: accession numbers: GSE58979 and GSE59045.Keywords: Gene Expression; IL8; Immune Regulation; Inflammatory Response.The incidence of fatty liver disease has 1increased inparallel to the global obesity pandemic and is predicted to become the most important indication for liver transplantation during the next decade. Adipose tissue is a mediator of metabolic and cardiovascular disorders in the general population, and has been implicated in the development of nonalcoholic fatty liver disease (NAFLD). 2 Abdominal adiposity, quantified by magnetic resonance imaging, correlates with steatosis in healthy individuals and with severity of inflammation and ...

Adipose tissue macrophages induce hepatic neutrophil recruitment and macrophage accumulation in mice

“…These data indicate that CD11c + (M1) and not CD11c − (M2) ATMs are associated with liver pathology in humans. This notion is in agreement with findings of du Plessis et al showing that CD11c + cells are more frequent in AT from patients with NASH compared with non-NASH patients and are of vital importance in NAFLD to NASH progression 11. Our human data also confirmed the data of sorted cell murine ATMs showing higher expression of neutrophil chemotaxis genes in CD11c + macrophages after HFD feeding.…”

“…In particular, CXCL1/CXCL8 and CXCL16 have been well described to recruit neutrophils in vivo, while CXCL14 is considered a strong chemoattractant of neutrophils based on in vitro assays 25 27–30. Interestingly, du Plessis et al previously described a correlation between CXCL8 and liver inflammation or NAS, further strengthening the importance of this inflammatory protein in liver pathology 11. Furthermore, inhibition of CXCL14 was shown to reduce hepatic damage and mortality in a murine hepatotoxicity model.…”

Prohibitin in Adipose and Immune Functions

“…Thus, metabolic and immunological processes often undergo parallel changes in normal physiology, during aging, and in various diseases. Some examples are: pregnancy-associated changes in metabolic and immune functions [46], caloric restriction-induced longevity [47], and obesity-linked metabolic impairment [48]. However, various factors that integrate adipose and immune functions in physiological and pathophysiological states are poorly understood (Box 1).…”

Editorial: novel association between serum Pentraxin‐2 levels and advanced fibrosis in well‐characterised patients with non‐alcoholic fatty liver disease

“…PTX-2 is synthesised in the liver mostly upon IL-6 adipokine stimulation, and it could be hypothesised that the presence of obesity influences production of this protein. du Plessis et al 7 recently reported that in patients undergoing bariatric surgery, adipose tissue demonstrates increased expression of genes that regulate inflammation, and adipocyte tissue macrophages produce increased levels of inflammatory cytokines compared with adipose tissue from controls. Interestingly, Verna et al did not elicit a significant association between BMI and PTX-2 levels, but acknowledge that their numbers may have been too small to demonstrate a correlation.…”