Lipid-binding proteins modulate ligand-dependent trans-activation by peroxisome proliferator-activated receptors and localize to the nucleus as well as the cytoplasm

Helledie, Torben; Antonius, Marianne; Sørensen, Rikke Guldberg; Hertzel, Ann V.; Bernlohr, David A.; Kølvraa, Steen; Kristiansen, Karsten; Mandrup, Susanne

doi:10.1016/s0022-2275(20)31967-2

Cited by 99 publications

(10 citation statements)

References 63 publications

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“…Wy14643 at concentrations at or below 10 mM exhibited PPARa selectivity, and L165041 at concentrations below 50 nM was a potent and highly speci®c activator of PPARd. In transactivation experiments using mouse PPARs, we found that TTA most ef®caciously activated PPARa (Helledie et al, 2000). 1 In this study using human PPARs we observed that TTA more ef®caciously and potently activated PPARd, whereas TTA-dependent activation of PPARa and PPARg was more modest.…”

Section: Discussionmentioning

confidence: 60%

“…HaCaT cells were transfected with a PPAR-responsive reporter construct and PPAR expression vectors, and then treated with Wy14643, L165041, and BRL49653, which are selective for PPARa, PPARd, and PPARg, respectively (Kliewer et al, 1994(Kliewer et al, , 1995Forman et al, 1995;Lehmann et al, 1995;Berger et al, 1999). In addition, we included the thiasubstituted fatty acid analog TTA that in a concentrationdependent manner has been shown to activate all three murine PPAR subtypes (Helledie et al, 2000). 1 Figure 4 illustrates the selectivity, ef®cacy, and potency of the different ligands.…”

Section: Resultsmentioning

confidence: 99%

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Modulation of Keratinocyte Gene Expression and Differentiation by PPAR-Selective Ligands and Tetradecylthioacetic Acid

Westergaard

Henningsen

Svendsen

et al. 2001

Journal of Investigative Dermatology

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230

213

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Peroxisome proliferator-activated receptors (PPARs) are pleiotropic regulators of growth and differentiation of many cell types. We have performed a comprehensive analysis of the expression of PPARs, transcriptional cofactors, and marker genes during differentiation of normal human keratinocytes using a combination of reverse transcriptase polymerase chain reaction, Northern and Western blotting, and immunohistochemistry. PPARdelta was the predominant PPAR subtype in human keratinocytes and highly expressed in basal cells and suprabasal cells. Induction of PPARalpha and PPARgamma expression was linked to differentiation, and accordingly, expression of PPARalpha and PPARgamma was in essence confined to suprabasal cells. Differentiation was not accompanied by significant changes in the expression of the coactivators CREB-binding protein, p300, steroid receptor coactivator 1, or the corepressors nuclear receptor corepressor and silence mediator for retinoid and thyroid hormone receptors. We critically evaluated the effects of selective PPAR ligands and a synthetic fatty acid analog, tetradecylthioacetic acid. Tetradecylthioacetic acid activated all human PPAR subtypes in the ranking order PPARdelta >> PPARalpha > PPARgamma. All selective PPAR ligands marginally induced transglutaminase-1 expression with the PPARdelta-selective ligand L165041 being the most potent. The PPARalpha- and PPARgamma-selective ligands Wy14643 and BRL49653 had negligible effect on involucrin expression, whereas a dose-dependent induction was observed with L165041. Simultaneous addition of L165041 and BRL49653 synergistically induced strong involucrin expression. Additionally, L165041 potently induced CD36 mRNA expression. Administration of tetradecylthioacetic acid resulted in a dramatic decrease in proliferation and a robust upregulation of the expression of involucrin and transglutaminase. Our results indicate that tetradecylthioacetic acid may affect keratinocyte gene expression and differentiation via PPAR-dependent and PPAR-independent pathways, and that the latter play an important role.

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Section: Discussionmentioning

confidence: 60%

Section: Resultsmentioning

confidence: 99%

Modulation of Keratinocyte Gene Expression and Differentiation by PPAR-Selective Ligands and Tetradecylthioacetic Acid

Westergaard

Henningsen

Svendsen

et al. 2001

Journal of Investigative Dermatology

Self Cite

230

213

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“…Previous reports also showed that FABP5 also localizes to the nucleus (Helledie et al, 2000;Napoli, 2016. The different results of FABP5 subcellular localization might be due to the different cell types. Since we observed that FABP5 is a cytoplasmic protein and the stimulation of FABP5 on SREBP-1c gene expression depends on its ability to effectively transport fatty acids, we speculate that fatty acids transported into cells by FABP5 directly or indirectly stimulate SREBP-1c gene expression.…”

Section: Discussionmentioning

confidence: 89%

FABP5 is a critical regulator of methionine‐ and estrogen‐induced SREBP‐1c gene expression in bovine mammary epithelial cells

Zhou

et al. 2018

Journal Cellular Physiology

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The intracellular fatty acid-binding proteins (FABPs) are a well-conserved family that function as lipid chaperones. Ongoing studies are focused on identification of the mechanistic complexity and vast biological diversity of different isoforms of FABPs. However, the molecular mechanism of FABP5 in the regulation of milk fat synthesis in the mammary gland of dairy cows is still largely unknown. Here, we report that FABP5 acts as a critical regulator of terol response element-binding protein-1c (SREBP-1c) gene expression induced by methionine (Met) and estrogen (E2) in bovine mammary epithelial cells (BMECs). We observed that the expression of FABP5 was markedly higher in dairy cow mammary tissue during the lactating period than the puberty period and the dry period. FABP5 is located in the cytoplasm, and Met and E2 significantly increase the protein levels of FABP5 in BMECs. Using gene function study approaches, we revealed that FABP5 positively regulates SREBP-1c gene expression and promotes milk fat synthesis. We confirmed that FABP5 is required for Met- and E2-induced SREBP-1c gene expression and milk fat synthesis. We further uncovered that fatty acids are needed for FABP5-mediated SREBP-1c gene expression. Thus, our study demonstrates that FABP5 is a critical regulator of Met- and E2-induced SREBP-1c gene expression leading to milk fat synthesis.

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“…Fatty Acid Binding Protein 5 (FABP5), one of the FABPs expressed in macrophages, is suggested to sequester antiinflammatory mediators from their target, creating a pro-inflammatory environment. [20][21][22] However, we have shown that FABP5-deficient mice develop increased inflammation following influenza A infection that persists long after wild type mice recovery, 23 likely indicating a complex role for FABP5 in modulating inflammatory responses in vivo.…”

Section: Introductionmentioning

confidence: 90%

Macrophage programming is regulated by a cooperative interaction between fatty acid binding protein 5 and peroxisome proliferator‐activated receptor γ

et al. 2022

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Resolution of inflammation is an active process that is tightly regulated to achieve repair and tissue homeostasis. In the absence of resolution, persistent inflammation underlies the pathogenesis of chronic lung disease such as chronic obstructive pulmonary disease (COPD) with recurrent exacerbations. Over the course of inflammation, macrophage programming transitions from pro‐inflammatory to pro‐resolving, which is in part regulated by the nuclear receptor Peroxisome Proliferator‐Activated Receptor γ (PPARγ). Our previous work demonstrated an association between Fatty Acid Binding Protein 5 (FABP5) expression and PPARγ activity in peripheral blood mononuclear cells of healthy and COPD patients. However, a role for FABP5 in macrophage programming has not been examined. Here, using a combination of in vitro and in vivo approaches, we demonstrate that FABP5 is necessary for PPARγ activation. In turn, PPARγ acts directly to increase FABP5 expression in primary human alveolar macrophages. We further illustrate that lack of FABP5 expression promotes a pro‐inflammatory macrophage programming with increased secretion of pro‐inflammatory cytokines and increased chromatin accessibility for pro‐inflammatory transcription factors (e.g., NF‐κB and MAPK). And finally, real‐time cell metabolic analysis using the Seahorse technology shows an inhibition of oxidative phosphorylation in FABP5‐deficient macrophages. Taken together, our data indicate that FABP5 and PPARγ reciprocally regulate each other's expression and function, consistent with a novel positive feedback loop between the two factors that mediates macrophage pro‐resolving programming. Our studies highlight the importance of defining targets and regulatory mechanisms that control the resolution of inflammation and may serve to inform novel interventional strategies directed towards COPD.

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Lipid-binding proteins modulate ligand-dependent trans-activation by peroxisome proliferator-activated receptors and localize to the nucleus as well as the cytoplasm

Cited by 99 publications

References 63 publications

Modulation of Keratinocyte Gene Expression and Differentiation by PPAR-Selective Ligands and Tetradecylthioacetic Acid

Modulation of Keratinocyte Gene Expression and Differentiation by PPAR-Selective Ligands and Tetradecylthioacetic Acid

FABP5 is a critical regulator of methionine‐ and estrogen‐induced SREBP‐1c gene expression in bovine mammary epithelial cells

Macrophage programming is regulated by a cooperative interaction between fatty acid binding protein 5 and peroxisome proliferator‐activated receptor γ

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