On the Role of Liver X Receptors in Lipid Accumulation in Adipocytes

Juvet, Lene Kristine; Andresen, Sissel M.; Schuster, Gertrud U.; Dalen, Knut Tomas; Tobin, Kari Anne R.; Hollung, Kristin; Haugen, Fred; Jacinto, Severina M.; Ulven, Stine Marie; Bamberg, Krister; Gustafsson, Jan‐Åke; Nebb, Hilde I.

doi:10.1210/me.2001-0210

Cited by 136 publications

(164 citation statements)

References 65 publications

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“…In addition, and most importantly, silencing LXR expression totally eliminates the response of the endogenous adipocyte apoE gene to PPAR␥ stimulation. Consistent with the observations of others (14,15), treatment of adipocytes with PPAR␥ agonists increases both total cellular and nuclear LXR protein. It is of interest that, despite this increase in LXR protein, the response of the apoE gene to the combined addition of a PPAR␥ and LXR agonist is not greater than that to either agonist alone.…”

Section: Discussionsupporting

confidence: 91%

“…Sterol efflux from differentiating adipocytes remains very limited despite induction of ABCA1 and apoE expression during adipocyte differentiation (19). Furthermore, treatment of adipocytes with LXR agonists, which stimulate apoE and ABCA1 expression, increases adipocyte lipid accumulation (15). We have shown that adipocyte apoE is required for optimal TG accumulation in adipocytes (6).…”

Section: Discussionmentioning

confidence: 84%

“…Based on considerations presented in the introduction, we focused on a potential intermediary role for the LXR pathway. The LXR gene has been shown to be a target of PPAR␥ agonists (14,15), and we examined the response of LXR protein levels in our model system. Fig.…”

Section: Methodsmentioning

confidence: 99%

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

Yue

Mazzone

2009

Journal of Biological Chemistry

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Peroxisome proliferator-activated receptor (PPAR␥) agonists increase insulin sensitivity in humans and are useful for treating human diabetes. Treatment with these agonists leads to increased apoE expression and triglyceride accumulation in adipocytes. The importance of apoE for adipocyte triglyceride accumulation is demonstrated by observations that triglyceride accumulation is impaired in apoE knockout adipocytes treated with PPAR␥ agonists. The current studies investigate the molecular mechanism for PPAR␥ stimulation of the adipocyte apoE gene and demonstrate that the liver receptor X (LXR) response element within an apoE gene downstream enhancer is required for the apoE response to PPAR␥ agonists. The response of the apoE gene to treatment with PPAR␥ agonists was delayed beyond 12 h suggesting the involvement of an intermediary pathway. The combined addition of PPAR␥ and LXR agonists did not increase apoE response beyond that observed with addition of either alone. Deletion or mutation of the LXR response element completely eliminated the adipocyte apoE gene response to a PPAR␥ agonist. Chromatin immunoprecipitation analyses performed using isolated adipocytes, or adipose tissue from mice treated with PPAR␥ agonists, showed increased LXR binding to the apoE gene after PPAR␥ agonist treatment. Knockdown of LXR expression completely eliminated the increase in apoE message, protein, and triglyceride in response to PPAR␥ stimulation. The LXR response element has been previously shown to mediate sterol responsiveness of the apoE gene, and apoE expression plays an important role in adipocyte triglyceride balance. The current observations suggest that the PPAR␥-LXR-apoE regulatory cascade could be an important molecular link for cross-talk between adipocyte triglyceride and cholesterol homeostasis. PPAR␥2 is highly expressed in adipocytes where it modulates the expression of a program of genes involved in adipocyte function (1). These include genes involved in TGD and fatty acid metabolism and in the expression of adipokines. Adipocyte lipid metabolism and the secretion of adipokines have a powerful effect on systemic substrate utilization and on overall organismal energy metabolism (2, 3). TZD drugs, currently in clinical use for treatment of human diabetes, are established ligands of adipocyte PPAR␥ receptors, and we have previously shown that adipocyte apoE expression is responsive to treatment with these drugs (4). 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). Reactive oxygen species produced by the stromovascular fracti...

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 84%

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

Yue

Mazzone

2009

Journal of Biological Chemistry

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“…Interestingly, this enhancer contains a conserved functional LXR response element. Because the expression of LXR␣ is positively regulated by PPAR␥ agonists in adipocytes (42)(43)(44)(45), this LXR element, in the presence of an endogenously generated ligand, could account for increased apoE gene expression in response to ciglitazone. On the other hand, a functional PPAR␥ response element has also been identified for transducing the apoE gene response to ciglitazone in U87MG astrocytoma cells (31).…”

Section: Discussionmentioning

confidence: 99%

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

Yue

Rasouli

Ranganathan

et al. 2004

Journal of Biological Chemistry

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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.

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“…First, NR1HRα and β are abundantly produced in adipocytes, preferentially in subcutaneous rather than in visceral white adipose tissue [9]. In addition, NR1HR production is regulated by the key adipocyte transcription factor PPARγ either in macrophages and in adipose tissue, and many NR1HR target genes are also highly expressed in adipocytes [10][11][12]. Moreover, ligand activation of NR1HR regulates production of the insulin-responsive glucose transporter solute carrier family 2 (facilitated glucose transporter), member 4 (SLC2A4, formerly known as GLUT4) both in vivo and in murine and human adipocytes, through direct interaction with a conserved NR1HR response element in the Slc2a4 promoter.…”

Section: Introductionmentioning

confidence: 99%

Liver X receptor agonists ameliorate TNFα-induced insulin resistance in murine brown adipocytes by downregulating protein tyrosine phosphatase-1B gene expression

et al. 2006

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Aims/hypothesis The nuclear receptors, including nuclear receptor subfamily 1, group H, member 3 (NR1HR, also known as liver X receptor [LXR]), are sensors of cholesterol metabolism and lipid biosynthesis that have recently been proposed as insulin sensitisers. TNFα has been described as a link between obesity and the development of insulin resistance, an important contributor to the pathogenesis of type 2 diabetes. Therefore, we decided to investigate the ability of NR1HR agonists to ameliorate TNFα-induced insulin resistance in brown adipocytes. Methods Primary brown adipocytes from rat fetuses, and from wild-type neonate mice and neonate mice deficient in the gene encoding protein tyrosine phosphatase-1B (Ptpn1, also known as Ptp1b) were cultured in the absence or presence of TNFα and different nuclear receptor agonists. Among them, the unrelated NR1HR ligands T0901317, GW3965 and (22R)-hydroxycholesterol were tested. After insulin stimulation, glucose uptake and solute carrier family 2 (facilitated glucose transporter), member 4 (SLC2A4, formerly known as GLUT4) translocation were measured. Next the insulin signalling cascade was determined by submitting cells to lysis, immunoprecipitation and immunoblotting. Results NR1HR agonists ameliorate TNFα-induced insulin resistance restoring completely insulin-stimulated glucose uptake and SLC2A4 translocation to plasma membrane. This effect is parallel to the recovery of the insulin cascade insulin receptor/IRS-2/phosphatidylinositol 3-kinase/protein kinase B, and could be due to the fact that T0901317 prevents the increase of PTPN1 production and phosphatase activity produced by TNFα. In this regard, Ptpn1-deficient brown adipocytes showed protection against insulin resistance by TNFα. Moreover, we observed that T0901317 produced in itself a significant increase over basal glucose uptake consistent with an increase of SLC2A4 protein content in plasma membrane, attributable to the activation of protein kinase ζ and/or the increase of Slc2a4 expression. Conclusions/interpretation Nuclear receptors NR1HR are interesting potential targets for drug treatment of insulin resistance. Keywords

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On the Role of Liver X Receptors in Lipid Accumulation in Adipocytes

Cited by 136 publications

References 65 publications

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

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

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

Liver X receptor agonists ameliorate TNFα-induced insulin resistance in murine brown adipocytes by downregulating protein tyrosine phosphatase-1B gene expression

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