Journal Article

Fetuin-A Induces Cytokine Expression and Suppresses Adiponectin Production

Wicke, Corinna, Machicao, Fausto, Hennige, Anita M., Fritsche, Andreas, Stefan, Norbert, Häring, Hans-Ulrich, Staiger, Harald

2008

Overview

The secreted liver protein fetuin-A (AHSG) is up-regulated in hepatic steatosis and the metabolic syndrome. These states are strongly associated with low-grade inflammation and hypoadiponectinemia. We, therefore, hypothesized that fetuin-A may play a role in the regulation of cytokine expression, the modulation of adipose tissue expression and plasma concentration of the insulin-sensitizing and atheroprotective adipokine adiponectin. Human monocytic THP1 cells and human in vitro differenttiated adipocytes as well as C57BL/6 mice were treated with fetuin-A. mRNA expression of the genes encoding inflammatory cytokines and the adipokine adiponectin (ADIPOQ) was assessed by real-time RT-PCR. In 122 subjects, plasma levels of fetuin-A, adiponectin and, in a subgroup, the multimeric forms of adiponectin were determined. Fetuin-A treatment induced TNF and IL1B mRNA expression in THP1 cells (p<0.05). Treatment of mice with fetuin-A, analogously, resulted in a marked increase in adipose tissue Tnf mRNA as well as Il6 expression (27- and 174-fold, respectively). These effects were accompanied by a decrease in adipose tissue Adipoq mRNA expression and lower circulating adiponectin levels (p<0.05, both). Furthermore, fetuin-A repressed ADIPOQ mRNA expression of human in vitro differentiated adipocytes (p<0.02) and induced inflammatory cytokine expression. In humans in plasma, fetuin-A correlated positively with high-sensitivity C-reactive protein, a marker of subclinical inflammation (r = 0.26, p = 0.01), and negatively with total- (r = -0.28, p = 0.02) and, particularly, high molecular weight adiponectin (r = -0.36, p = 0.01). We provide novel evidence that the secreted liver protein fetuin-A induces low-grade inflammation and represses adiponectin production in animals and in humans. These data suggest an important role of fatty liver in the pathophysiology of insulin resistance and atherosclerosis.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Adipocytes / Adiponectin / Adiponectin - biosynthesis / Adiponectin - blood / Adiponectin - genetics / Adipose tissue / alpha-Fetoproteins - physiology / Animals / Arteriosclerosis / Atherosclerosis / Blood Glucose - analysis / C-reactive protein / Cell Biology/Gene Expression / Cell Line / Cytokines / Cytokines - metabolism / Diabetes / Diabetes and Endocrinology / Diabetes and Endocrinology/Obesity / Diabetes and Endocrinology/Type 2 Diabetes / Endocrinology / Endothelium / Enzyme-Linked Immunosorbent Assay / Fatty liver / Gangrene / Gene expression / House mouse / Humans / Inflammation / Insulin / Insulin resistance / Interleukin 1 / Interleukin 6 / Internal medicine / Kinases / Laboratory animals / Liver / Male / Medicine / Metabolic disorders / Metabolic syndrome / Mice / Mice, Inbred C57BL / Molecular weight / Monocytes / Nephrology / Obesity / Pathogenesis / Penicillin / Physiology/Endocrinology / Physiology/Integrative Physiology / Plasma levels / Plasmas (physics) / Polymerase chain reaction / Proteins / Reverse Transcriptase Polymerase Chain Reaction / RNA / RNA, Messenger - genetics / Rodents / Sensitizing / Steatosis / Tumor necrosis factor / Tumor necrosis factor-TNF / Type 2 diabetes