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.
