Potential Role of Tumor Necrosis Factor-α in Downregulating Sex Hormone–Binding Globulin

Abstract

Low plasma sex hormone–binding globulin (SHBG) levels are associated with obesity and predict the development of type 2 diabetes. The reason why obese individuals have low circulating SHBG has been attributed to hyperinsulinemia, but no mechanistic evidence has been described. The aim of the current study is to explore whether tumor necrosis factor-α (TNF-α) rather than insulin could be the main factor accounting for low SHBG levels in obesity. We performed in vitro and in vivo studies using human HepG2 cells and human SHBG transgenic mice. In addition, a cross-sectional study to explore the relationship between TNF-α and SHBG in obese patients and an interventional study to examine the effect of insulin administration on circulating SHBG in type 2 diabetic patients were performed. We provide evidence that TNF-α, but not insulin, is the main factor by which SHBG is reduced in obesity. Plasma SHBG was significantly increased rather than decreased after insulin treatment in diabetic patients. TNF-α–induced reduction of SHBG expression was mediated by downregulating HNF4A. Finally, a negative and independent correlation was found between plasma TNF-α receptor 1 and SHBG levels in obese patients. Our results suggest that TNF-α plays an important role downregulating SHBG in chronic low-grade inflammatory diseases such as obesity and type 2 diabetes.

Novel insights in SHBG regulation and clinical implications

“…Moreover, daily treatment with TNFa reduced plasma SHBG levels through NF-kB in hSHBG mice [35]. Finally, a negative and independent correlation was found between plasma TNFa receptor 1 and SHBG levels in obese patients [35]. These findings are supported by results from older studies in humans with chronic inflammatory disease such as rheumatoid arthritis or osteoarthritis, in which both TNFa activation and low SHBG levels have been reported [32].…”

“…The effect of TNFa on SHBG expression was indirect and was mediated by nuclear factor kappa B (NF-kB) through the downregulation of HNF-4a mRNA and protein levels in HepG2 cells ( Figure 1). Moreover, daily treatment with TNFa reduced plasma SHBG levels through NF-kB in hSHBG mice [35]. Finally, a negative and independent correlation was found between plasma TNFa receptor 1 and SHBG levels in obese patients [35].…”

“…Recent in vitro studies provide evidence that TNFa reduces SHBG production in HepG2 cells [35,36]. The effect of TNFa on SHBG expression was indirect and was mediated by nuclear factor kappa B (NF-kB) through the downregulation of HNF-4a mRNA and protein levels in HepG2 cells ( Figure 1).…”

“…These early studies used HepG2 cells grown in serum-free medium for at least 1 week during insulin treatment, without replacing or supplementing the medium to allow the accumulation of SHBG to be measured [44,48,49]. More recently, studies performed under more physiological conditions, in which the growth medium was supplemented with untreated or heatinactivated fetal bovine serum, have showed that insulin does not regulate SHBG production in HepG2 cells [35,50]. However, HepG2, being transformed cells, cannot reflect the biology of normal cells.…”

Hepatocyte nuclear factor 4 alpha promotes the invasion, metastasis and angiogenesis of neuroblastoma cells via targeting matrix metalloproteinase 14

“…Human HNF4α expression vector was provided by Dr. David Martinez Selva [22]. The oligonucleotides encoding short hairpin RNA (shRNA) specific for HNF4α (sh-HNF4α) and scramble shRNA (sh-Scb) were subcloned into GV248 (Genechem Co., Ltd, Shanghai, China; Supplementary Table S2).…”