GW501516 acts as an efficient PPARα activator in the mouse liver

Terada, Masahiro; Araki, Makoto; Ashibe, Bunichiro; Motojima, Kiyoto

doi:10.5582/ddt.2011.v5.4.176

Cited by 6 publications

(5 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Despite being designed as a PPARd-specific ligand, GW has been suggested to activate PPARa directly when used in micromolar concentrations (16). Alternatively, activation of PPARa downstream of GW-mediated PPARd activation has also been suggested (17).…”

Section: Resultsmentioning

confidence: 99%

Activation of Peroxisome Proliferator-Activated Receptors α and δ Synergizes with Inflammatory Signals to Enhance Adoptive Cell Therapy

et al. 2019

View full text Add to dashboard Cite

Memory CD8 þ T cells (T mem ) are superior mediators of adoptive cell therapy (ACT) compared with effector CD8 þ T cells (T eff ) due to increased persistence in vivo. Underpinning T mem survival is a shift in cellular metabolism away from aerobic glycolysis towards fatty acid oxidation (FAO). Here we investigated the impact of the peroxisome proliferator-activated receptor (PPAR) agonist GW501516 (GW), an agent known to boost FAO in other tissues, on CD8 þ T-cell metabolism, function, and efficacy in a murine ACT model. Via activation of both PPARa and PPARd/b, GW treatment increased expression of carnitine palmitoyl transferase 1a, the rate-limiting enzyme of FAO, in activated CD8 þ T cells. Using a metabolomics approach, we demonstrated that GW increased the abundance of multiple different acylcarnitines, consistent with enhanced FAO. T cells activated in the presence of GW and inflammatory signals, either mature dendritic cells or IL12, also demonstrated enhanced production of IFNg and expression of T-bet. Despite high expression of T-bet, a characteristic of short-lived effector cells, GW-treated cells demonstrated enhanced persistence in vivo and superior efficacy in a model of ACT. Collectively, these data identify combined PPARa and PPARd/b agonists as attractive candidates for further studies and rapid translation into clinical trials of ACT.Significance: Dual activation of peroxisome proliferatoractivated receptors a and d improves the efficacy of adoptive cell therapy by reprogramming T-cell metabolism and cytokine expression.Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis):

show abstract

Section: Resultsmentioning

confidence: 99%

Activation of Peroxisome Proliferator-Activated Receptors α and δ Synergizes with Inflammatory Signals to Enhance Adoptive Cell Therapy

et al. 2019

View full text Add to dashboard Cite

show abstract

“…Although Terada and colleagues [ 58 ] discussed two possibilities in which one of them was that GW501516 might act as direct activator of PPAR α in the absence of PPAR δ , weight loss or hepatic steatosis was not observed in GW501516 treated PPAR δ -KO mice (Figures 4(a) and 4(c) ), demonstrating that activation of PPAR α by GW501516 is not sufficient to induce these responses. While GW501516 can act directly upon PPAR α to generate some phenotypes attributed also to PPAR δ such as lowering plasma TG or regulating common set of genes (such as Acox1), the collaboration between these two members of the same family is essential for weight loss initiation and hepatic lipid regulation ( Figure 4(g) ).…”

Section: Discussionmentioning

confidence: 99%

PPARαIs Required for PPARδAction in Regulation of Body Weight and Hepatic Steatosis in Mice

et al. 2015

View full text Add to dashboard Cite

Peroxisome proliferator activated receptors alpha (PPARα) and delta (PPARδ) belong to the nuclear receptor superfamily. PPARα is a target of well established lipid-lowering drugs. PPARδ (also known as PPARβ/δ) has been investigated as a promising antidiabetic drug target; however, the evidence in the literature on PPARδ effect on hepatic lipid metabolism is inconsistent. Mice conditionally expressing human PPARδ demonstrated pronounced weight loss and promoted hepatic steatosis when treated with GW501516 (PPARδ-agonist) when compared to wild type mice. This effect was completely absent in mice with either a dominant negative form of PPARδ or deletion of the DNA binding domain of PPARδ. This confirmed the absolute requirement for PPARδ in the physiological actions of GW501516 and confirmed the potential utility against the human form of this receptor. Surprisingly the genetic deletion of PPARα also abrogated the effect of GW501516 in terms of both weight loss and hepatic lipid accumulation. Also the levels of the PPARα endogenous agonist 16:0/18:1-GPC were shown to be modulated by PPARδ in wild type mice. Our results show that both PPARδ and PPARα receptors are essential for GW501516-driven adipose tissue reduction and subsequently hepatic steatosis, with PPARα working downstream of PPARδ.

show abstract

“…Hepatic Vldlr in mice can be upregulated with fenofibrate through PPARɑ 21,[69][70][71] activation, suggesting a conserved mechanism within the fibrate class, which likely translates to humans. Fibrates have shown success in some, but fallen short of expectations in other clinical trials 72 , with different outcomes between men and women 31 .…”

Section: Discussionmentioning

confidence: 99%

“…Fenofibrate in mice reduces circulating TAGs through the upregulation of hepatic Vldlr, thereby increasing hepatic lipoprotein intake. This effect is achieved by activating Vldlr's transcriptional regulator PPARɑ 21,[68][69][70] . Fibrates have shown success in some, but fallen short of expectations in other clinical trials 71 , with different outcomes between men and women 41 .…”

Section: Discussionmentioning

confidence: 99%

A sexually dimorphic hepatic cycle of periportal VLDL generation and subsequent pericentral VLDLR-mediated lipoprotein re-uptake

Martini,

Gobet,

Salati

et al. 2023

Preprint

View full text Add to dashboard Cite

The liver shows striking sexual dimorphism, which is reflected in differences between women and men in pathologies inherently associated with hepatic function. Recent single-cell transcriptomes revealed spatiotemporal programmes of liver function on the sublobular scale. However, how sexual dimorphism affects this space-time logic remains poorly understood. To address this, we performed single-cell RNA-seq in the mouse liver, which allowed us to model how lobular position, circadian time and sex shape the transcriptome. We found that sex, space and time markedly influence xenobiotic detoxification and lipid processing, including lipoprotein metabolism. Crucially, the very low density lipoprotein receptor (VLDLR) is restricted to the pericentral zone, with significantly higher mRNA and protein levels in female mice, which is conserved in the human liver. In addition, several genes involved in VLDL assembly are periportally biased, and we corroborated periportal VLDL generation with electron microscopy. Together, this suggests a hepatic cycle of periportal formation and pericentral uptake of VLDL. In addition, we demonstrated that in humans VLDLR expression depends also on age and body mass index. Crucially, these processes provide a new window into the sexual dimorphism characterizing atherosclerotic cardiovascular disease.

show abstract

GW501516 acts as an efficient PPARα activator in the mouse liver

Cited by 6 publications

References 21 publications

Activation of Peroxisome Proliferator-Activated Receptors α and δ Synergizes with Inflammatory Signals to Enhance Adoptive Cell Therapy

Activation of Peroxisome Proliferator-Activated Receptors α and δ Synergizes with Inflammatory Signals to Enhance Adoptive Cell Therapy

PPARαIs Required for PPARδAction in Regulation of Body Weight and Hepatic Steatosis in Mice

A sexually dimorphic hepatic cycle of periportal VLDL generation and subsequent pericentral VLDLR-mediated lipoprotein re-uptake

Contact Info

Product

Resources

About