Regulation of expression of apolipoprotein A-I by selenium status in human liver hepatoblastoma cells.

BACKGROUND: Cardiomyopathy is common to areas with low selenium (Se) intake and in patients receiving total parenteral nutrition. Although controversial, a few studies have suggested a protective role for Se in coronary heart disease on the basis of modulation of high-density lipoproteins (HDL). AIMS OF THE STUDY: In this study, the role of Se as a positive regulator of expression of a key HDL, apolipoprotein A-I (apoA-I), has been evaluated in human hepatoblastoma (HepG2) cell culture model. We further examined if the transcription of apoA-I, driven by the nuclear hormone receptor, peroxisome-proliferator activated receptor, PPARalpha, was trans-repressed by the presence of the oxidative stress-responsive transcription factor, NF-kappaB. METHODS: Modulation of expression of apoA-I and activation of nuclear NF-kappaB subunit p65 and PPARalpha by Se status were evaluated by Western blot and luciferase-based assays. Interaction of p65 with PPARalpha was evaluated by immunoprecipitation. RESULTS: HepG2 cultured in media with Se (100 nM) demonstrated an increase in the expression of apoA-I when compared to Se-deficient cells. A similar trend was also seen in mice that were supplemented with 0.4 ppm of Se as sodium selenite. Treatment of Se-supplemented cells with bacterial lipopolysaccharide (LPS) showed induction of apoA-I. Supplementation of hepatocytes with Se decreased the nuclear levels of p65, which prevented its interaction with PPARalpha to modulate apoA-I transcription. CONCLUSION: Our results suggest that supplementation of hepatocytes with Se mitigates oxidative stress-dependent repression of apoA-I expression by suppressing the NF-kappaB pathway, which allows PPARalpha to effectively drive the expression of apoA-I.

Selenium attenuates pro-inflammatory gene expression in macrophages.

Selenium (Se) is an important element required for the optimal functioning of the immune system. Particularly in macrophages, which play a pivotal role in immune regulation, Se acts as a major antioxidant in the form of selenoproteins to mitigate the cytotoxic effects of reactive oxygen species. Here we describe the role of Se as an anti-inflammatory agent and its effect on the macrophage signal transduction pathways elicited by bacterial endotoxin, LPS. Our studies demonstrate that supplementation of Se to macrophages (Se-deficient) leads to a significant decrease in the LPS-induced expression of two important pro-inflammatory genes, cyclooxygenase-2 (COX-2) and tumor necrosis factor-alpha (TNF-alpha) via the inhibition of MAP kinase pathways. Furthermore, Se-deficiency in mice exacerbated the LPS-mediated infiltration of macrophages into the lungs suggesting that Se status is a crucial host factor that regulates inflammation. In summary, our results indicate that Se plays an important role as an anti-inflammatory agent by tightly regulating the expression of pro-inflammatory genes in immune cells.