Divergent Effects of Peroxisome Proliferator-activated Receptor γ Agonists and Tumor Necrosis Factor α on Adipocyte ApoE Expression

Abstract

ApoE is expressed in multiple mammalian cell types in which it supports cellular differentiated function. In this report we demonstrate that apoE expression in adipocytes is regulated by factors involved in modulating systemic insulin sensitivity. Systemic treatment with pioglitazone increased systemic insulin sensitivity and increased apoE mRNA levels in adipose tissue by 2-3-fold. Treatment of cultured 3T3-L1 adipocytes with ciglitazone increased apoE mRNA levels by 2-4-fold in a dose-dependent manner and increased apoE secretion from cells. Conversely, treatment of adipocytes with tumor necrosis factor (TNF) ␣ reduced apoE mRNA levels and apoE secretion by 60%. Neither insulin nor a peroxisome proliferator-activated receptor (PPAR) ␣ agonist regulated adipocyte apoE gene expression. In addition, treatment of human monocyte-derived macrophages with ciglitazone did not regulate expression of apoE. Additional analyses using reporter genes indicated that the effect of TNF␣ and PPAR␥ agonists on the apoE gene was mediated via distinct gene control elements. The TNF␣ effect was mediated by elements within the proximal promoter, whereas the PPAR␥ effect was mediated by elements within a downstream enhancer. However, the addition of TNF␣ substantially reduced the absolute levels of apoE reporter gene response even in the presence of ciglitazone. These results indicate for the first time that adipose tissue expression of apoE is modulated by physiologic regulators of insulin sensitivity.

Nuclear receptors agonists exert opposing effects on the inflammation dependent survival of breast cancer stem cells

“…28,29 PPARa also regulates the expression of lipoprotein receptors and cholesterol transporters, as apolipoprotein E (ApoE), that contains a PPRE sequence on its promoter. 39 Intriguingly, ApoE over-expression has been documented in normal MS 33 and in prostate CSCs. 14 We here observed that ApoE gene is over-expressed in T-MS compared with N-MS, and that ApoE expression is regulated by PPRAa expression in MCF7-MS (Supplementary Figure 6).…”

Peroxisome Proliferator-activated Receptor γ Stimulation of Adipocyte ApoE Gene Transcription Mediated by the Liver Receptor X Pathway

“…The dose-related increase with rosiglitazone establishes the apoE response after treatment of adipocytes with three different PPAR␥ agonists, rosiglitazone (Fig. 1A), ciglitazone, and pioglitazone (4,6). The time course for the response of the apoE gene to treatment with rosiglitazone ( Fig.…”

“…Treating isolated adipocytes or intact humans with PPAR␥ agonists increases adipocyte and adipose tissue apoE gene expression (4,6). The proinflammatory cytokine, tumor necrosis factor-␣, reduces adipocyte apoE expression, an effect mediated by the NF-B transcriptional complex binding an element in the apoE gene proximal promoter (4,7). Reactive oxygen species produced by the stromovascular fraction of adipose tissue harvested from obese mice also reduce adipocyte apoE expression via the NF-B pathway (8).…”

“…Zechner and colleagues first described expression of apoE by adipocytes in 1991 (5), but only recently has additional information been provided regarding regulation and function of adipocyte apoE (6 -10). Treating isolated adipocytes or intact humans with PPAR␥ agonists increases adipocyte and adipose tissue apoE gene expression (4,6). The proinflammatory cytokine, tumor necrosis factor-␣, reduces adipocyte apoE expression, an effect mediated by the NF-B transcriptional complex binding an element in the apoE gene proximal promoter (4,7).…”

“…In previous studies, we established that the response of the apoE gene to PPAR␥ agonists was not mediated by the apoE proximal promoter but required the presence of at least one of these two apoE downstream gene enhancers (4). Based on the requirement for a downstream enhancer, the presence of an LXRE in the enhancer, the absence of a clearly identifiable PPRE within this enhancer, and the recently established posi-tive effect of PPAR␥ agonists on LXR gene transcription (14), we hypothesized that the response of the adipocyte apoE gene to PPAR␥ agonists could be mediated by the LXR pathway (4).…”