CD36-dependent fatty acid uptake regulates expression of peroxisome proliferator activated receptors

2005 ◽  
Vol 33 (1) ◽  
pp. 311-315 ◽  
Author(s):  
V.A. Drover ◽  
N.A. Abumrad
Keyword(s):  
Plasma Lipids ◽  
Fatty Acid Uptake ◽  
Peroxisome Proliferator ◽  
Acid Uptake ◽  
Mrna Levels ◽  
Peroxisome Proliferator Activated Receptor ◽  
Peroxisome Proliferator Activated Receptors ◽  
Induced Changes ◽  
Deficient Mice

CD36 is an important regulator of lipid metabolism in vivo due to its role in the facilitated uptake of long-chain FAs (fatty acids). CD36-deficient mice display reduced TAG (triacylglycerol) in muscle, but elevated hepatic TAG. Also, insulin sensitivity is enhanced peripherally, while it appears impaired in the liver [Goudriaan, Dahlmans, Teusink, Ouwens, Febbraio, Maassen, Romijn, Havekes, and Voshol (2003) J. Lipid. Res. 44, 2270–2277; and Hajri, Han, Bonen and Abumrad (2002) J. Clin. Invest. 109, 1381–1389]. Tissues such as muscle, which normally express high levels of CD36, shift to high glucose utilization in CD36 deficiency [Hajri, Han, Bonen and Abumrad (2002) J. Clin. Invest. 109, 1381–1389], so we hypothesized that this shift must involve adaptive changes in the PPAR (peroxisome-proliferator-activated receptor) transcription factors which regulate FA metabolism. To test this, we examined mRNA levels for the three PPAR isoforms in tissues of WT (wild-type) and CD36-deficient mice following the administration of saline, glucose or olive oil by intragastric gavage. Compared with WT mice, CD36-null mice had 5–10-fold increased PPAR mRNA in adipose tissue in the basal state, and did not exhibit diet-induced changes. Correlations between adipose PPAR mRNA abundance and plasma lipids were observed in WT mice, but not in CD36-null mice. The opposite was true for hepatic PPAR mRNA levels, which correlated with plasma FA, TAG and/or glucose only in CD36-null mice. No significant differences were observed in PPAR mRNA levels in the intestine, where CD36 does not impact on FA uptake. The data suggest that CD36 and the PPARs are components of the FA-sensing machinery to respond to changes in FA flux in a tissue-specific manner.

scholarly journals Association with Coregulators Is the Major Determinant Governing Peroxisome Proliferator-activated Receptor Mobility in Living Cells

2006 ◽  
Vol 282 (7) ◽  
pp. 4417-4426 ◽  
Author(s):  
Cicerone Tudor ◽  
Jérôme N. Feige ◽  
Harikishore Pingali ◽  
Vidya Bhushan Lohray ◽  
Walter Wahli ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Molecular Mechanisms ◽  
Resonance Energy Transfer ◽  
Resonance Energy ◽  
Living Cells ◽  
Correlation Spectroscopy ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Peroxisome Proliferator Activated Receptors

The nucleus is an extremely dynamic compartment, and protein mobility represents a key factor in transcriptional regulation. We showed in a previous study that the diffusion of peroxisome proliferator-activated receptors (PPARs), a family of nuclear receptors regulating major cellular and metabolic functions, is modulated by ligand binding. In this study, we combine fluorescence correlation spectroscopy, dual color fluorescence cross-correlation microscopy, and fluorescence resonance energy transfer to dissect the molecular mechanisms controlling PPAR mobility and transcriptional activity in living cells. First, we bring new evidence that in vivo a high percentage of PPARs and retinoid X receptors is associated even in the absence of ligand. Second, we demonstrate that coregulator recruitment (and not DNA binding) plays a crucial role in receptor mobility, suggesting that transcriptional complexes are formed prior to promoter binding. In addition, association with coactivators in the absence of a ligand in living cells, both through the N-terminal AB domain and the AF-2 function of the ligand binding domain, provides a molecular basis to explain PPAR constitutive activity.

Prenatal androgen excess alters the uterine peroxisome proliferator-activated receptor (PPAR) system

2019 ◽  
Vol 31 (8) ◽  
pp. 1401
Author(s):  
Silvana R. Ferreira ◽  
Leandro M. Vélez ◽  
Maria F. Heber ◽  
Giselle A. Abruzzese ◽  
Alicia B. Motta
Keyword(s):  
Fetal Programming ◽  
Female Offspring ◽  
Control Group ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Androgen Excess ◽  
Peroxisome Proliferator Activated Receptor ◽  
Peroxisome Proliferator Activated Receptors ◽  
Pg E2 ◽  
Prenatal Androgen

It is known that androgen excess induces changes in fetal programming that affect several physiological pathways. Peroxisome proliferator-activated receptors (PPARs) α, δ and γ are key mediators of female reproductive functions, in particular in uterine tissues. Thus, we aimed to study the effect of prenatal hyperandrogenisation on the uterine PPAR system. Rats were treated with 2mg testosterone from Day 16 to 19 of pregnancy. Female offspring (PH group) were followed until 90 days of life, when they were killed. The PH group exhibited an anovulatory phenotype. We quantified uterine mRNA levels of PPARα (Ppara), PPARδ (Ppard), PPARγ (Pparg), their regulators peroxisome proliferator-activated receptor gamma coactivator 1-alpha (Ppargc1a) and nuclear receptor co-repressor 1 (Ncor1) and cyclo-oxygenase (COX)-2 (Ptgs2), and assessed the lipid peroxidation (LP) index and levels of glutathione (GSH) and prostaglandin (PG) E2. The PH group showed decreased levels of all uterine PPAR isoforms compared with the control group. In addition, PGE2 and Ptgs2 levels were increased in the PH group, which led to a uterine proinflammatory environment, as was LP, which led to a pro-oxidant status that GSH was not able to compensate for. These results suggest that prenatal exposure to androgen excess has a fetal programming effect that affects the gene expression of PPAR isoforms, and creates a misbalanced oxidant–antioxidant state and a proinflammatory status.

scholarly journals Ligand-Activated Peroxisome Proliferator Activated Receptor γ Alters Placental Morphology and Placental Fatty Acid Uptake in Mice

Endocrinology ◽  
2007 ◽  
Vol 148 (8) ◽  
pp. 3625-3634 ◽  
Author(s):  
W. Timothy Schaiff ◽  
F. F. (Russ) Knapp ◽  
Yaacov Barak ◽  
Tal Biron-Shental ◽  
D. Michael Nelson ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Transport ◽  
Peroxisome Proliferator ◽  
Acid Uptake ◽  
Acid Transport ◽  
Placental Development ◽  
Peroxisome Proliferator Activated Receptor ◽  
Altered Expression ◽  
Pparγ Agonist

The nuclear receptor peroxisome proliferator activated receptor γ (PPARγ) is essential for murine placental development. We previously showed that activation of PPARγ in primary human trophoblasts enhances the uptake of fatty acids and alters the expression of several proteins associated with fatty acid trafficking. In this study we examined the effect of ligand-activated PPARγ on placental development and transplacental fatty acid transport in wild-type (wt) and PPARγ+/− embryos. We found that exposure of pregnant mice to the PPARγ agonist rosiglitazone for 8 d (embryonic d 10.5–18.5) reduced the weights of wt, but not PPARγ+/− placentas and embryos. Exposure to rosiglitazone reduced the thickness of the spongiotrophoblast layer and the surface area of labyrinthine vasculature, and altered expression of proteins implicated in placental development. The expression of fatty acid transport protein 1 (FATP1), FATP4, adipose differentiation related protein, S3-12, and myocardial lipid droplet protein was enhanced in placentas of rosiglitazone-treated wt embryos, whereas the expression of FATP-2, -3, and -6 was decreased. Additionally, rosiglitazone treatment was associated with enhanced accumulation of the fatty acid analog 15-(p-iodophenyl)-3-(R, S)-methyl pentadecanoic acid in the placenta, but not in the embryos. These results demonstrate that in vivo activation of PPARγ modulates placental morphology and fatty acid accumulation.

scholarly journals Control of human carnitine palmitoyltransferase II gene transcription by peroxisome proliferator-activated receptor through a partially conserved peroxisome proliferator-responsive element

2003 ◽  
Vol 369 (3) ◽  
pp. 721-729 ◽  
Author(s):  
María J. BARRERO ◽  
Nuria CAMARERO ◽  
Pedro F. MARRERO ◽  
Diego HARO
Keyword(s):  
Consensus Sequence ◽  
Carnitine Palmitoyltransferase ◽  
Proximal Promoter ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Peroxisome Proliferator Activated Receptors ◽  
Responsive Element ◽  
Carnitine Palmitoyltransferase Ii ◽  
Half Site

The expression of several genes involved in fatty acid metabolism is regulated by peroxisome proliferator-activated receptors (PPARs). To gain more insight into the control of carnitine palmitoyltransferase (CPT) gene expression, we examined the transcriptional regulation of the human CPT II gene. We show that the 5′-flanking region of this gene is transcriptionally active and binds PPARα in vivo in a chromatin immunoprecipitation assay. In addition, we characterized the peroxisome proliferator-responsive element (PPRE) in the proximal promoter of the CPT II gene, which appears to be a novel PPRE. The sequence of this PPRE contains one half-site which is a perfect consensus sequence (TGACCT) but no clearly recognizable second half-site (CAGCAC); this part of the sequence contains only one match to the consensus, which seems to be irrelevant for the binding of PPARα. As expected, other members of the nuclear receptor superfamily also bind to this element and repress the activation mediated by PPARα, thus showing that the interplay between several nuclear receptors may regulate the entry of fatty acids into the mitochondria, a crucial step in their metabolism.

Perturbation of glucose flux in the liver by decreasing F26P2 levels causes hepatic insulin resistance and hyperglycemia

2006 ◽  
Vol 291 (3) ◽  
pp. E536-E543 ◽  
Author(s):  
Chaodong Wu ◽  
Salmaan A. Khan ◽  
Li-Jen Peng ◽  
Honggui Li ◽  
Steven G. Carmella ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Hepatic Insulin Resistance ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Peroxisome Proliferator Activated Receptor ◽  
Glucose Flux ◽  
Hepatic Glucose

Hepatic insulin resistance is one of the characteristics of type 2 diabetes and contributes to the development of hyperglycemia. How changes in hepatic glucose flux lead to insulin resistance is not clearly defined. We determined the effects of decreasing the levels of hepatic fructose 2,6-bisphosphate (F26P2), a key regulator of glucose metabolism, on hepatic glucose flux in the normal 129J mice. Upon adenoviral overexpression of a kinase activity-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase, the enzyme that determines F26P2 level, hepatic F26P2 levels were decreased twofold compared with those of control virus-treated mice in basal state. In addition, under hyperinsulinemic conditions, hepatic F26P2 levels were much lower than those of the control. The decrease in F26P2 leads to the elevation of basal and insulin-suppressed hepatic glucose production. Also, the efficiency of insulin to suppress hepatic glucose production was decreased (63.3 vs. 95.5% suppression of the control). At the molecular level, a decrease in insulin-stimulated Akt phosphorylation was consistent with hepatic insulin resistance. In the low hepatic F26P2 states, increases in both gluconeogenesis and glycogenolysis in the liver are responsible for elevations of hepatic glucose production and thereby contribute to the development of hyperglycemia. Additionally, the increased hepatic gluconeogenesis was associated with the elevated mRNA levels of peroxisome proliferator-activated receptor-γ coactivator-1α and phospho enolpyruvate carboxykinase. This study provides the first in vivo demonstration showing that decreasing hepatic F26P2 levels leads to increased gluconeogenesis in the liver. Taken together, the present study demonstrates that perturbation of glucose flux in the liver plays a predominant role in the development of a diabetic phenotype, as characterized by hepatic insulin resistance.

scholarly journals Modulation of peroxisome proliferator-activated receptor δ and γ transcripts in swine endometrial tissue during early gestation

Reproduction ◽  
2006 ◽  
Vol 131 (5) ◽  
pp. 929-942 ◽  
Author(s):  
Etienne Lord ◽  
Bruce D Murphy ◽  
Joëlle A Desmarais ◽  
Sandra Ledoux ◽  
Danièle Beaudry ◽  
...  
Keyword(s):  
Embryo Implantation ◽  
Endometrial Tissue ◽  
Pcr Analysis ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Tissue Sampling ◽  
Peroxisome Proliferator Activated Receptor ◽  
Attachment Sites ◽  
Peroxisome Proliferator Activated Receptors ◽  
Implantation Period

Recent evidence points to a role for peroxisome proliferator-activated receptors (PPARs) δ and γ in embryo implantation and survival. In this study, we report the porcine PPARδ complete coding sequence and mRNA abundance of PPARδ, PPARγ1 and γ2, angiopoietin-like protein 4 (ANGPTL4) and adipocyte determination and differentiation-dependent factor 1 (ADD1) genes in the pregnant sow endometrium. Real-time PCR analysis was used to study the effect of parity (Yorkshire-Landrace multiparous (YL) and nulliparous (YLn)), site of endometrial tissue sampling (between and at embryo attachment sites) in crossbred Duroc×Yorkshire-Landrace (DYL) sows and stages of pregnancy (non-pregnant, day 15 and day 25 after mating) in Meishan-Landrace (ML) on mRNA levels. Parity effects were observed for PPARδ, ANGPTL4, and ADD1, with higher mRNA levels in YL than YLn sows. In DYL sows, lower mRNA levels were present at attachment sites compared to between attachment sites for PPARδ, PPARγ1, and ANGPTL4. Finally, day 15 pregnant ML sows had lower PPARδ mRNA levels compared to day 15 cycling ML sows. A significant increase of PPARγ1 mRNA levels was found on day 25 pregnant ML and DYL sows relative to day 15 ML or DYL pregnant sows. PPARδ and γ immunostaining was detected in endometrial tissue of day 15 cycling sows, day 15 and 25 pregnant sows and epithelial cells of day 25 embryos. Collectively, our results suggest a role for PPARδ, PPARγ1, and ANGPTL4, but not PPARγ2, during the peri-implantation period in pregnant sows.

scholarly journals Endogenous Peroxisome Proliferator-Activated Receptor-γ Augments Fatty Acid Uptake in Oxidative Muscle

Endocrinology ◽  
2008 ◽  
Vol 149 (11) ◽  
pp. 5374-5383 ◽  
Author(s):  
Andrew W. Norris ◽  
Michael F. Hirshman ◽  
Jianrong Yao ◽  
Niels Jessen ◽  
Nicolas Musi ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Uptake ◽  
Transport Protein ◽  
Fatty Acid Transport ◽  
Peroxisome Proliferator ◽  
Acid Uptake ◽  
Acid Transport ◽  
Peroxisome Proliferator Activated Receptor ◽  
Nonesterified Fatty Acids ◽  
Fatty Acid Transport Protein

In the setting of insulin resistance, agonists of peroxisome proliferator-activated receptor (PPAR)-γ restore insulin action in muscle and promote lipid redistribution. Mice with muscle-specific knockout of PPARγ (MuPPARγKO) develop excess adiposity, despite reduced food intake and normal glucose disposal in muscle. To understand the relation between muscle PPARγ and lipid accumulation, we studied the fuel energetics of MuPPARγKO mice. Compared with controls, MuPPARγKO mice exhibited significantly increased ambulatory activity, muscle mitochondrial uncoupling, and respiratory quotient. Fitting with this latter finding, MuPPARγKO animals compared with control siblings exhibited a 25% reduction in the uptake of the fatty acid tracer 2-bromo-palmitate (P < 0.05) and a 13% increase in serum nonesterified fatty acids (P = 0.05). These abnormalities were associated with no change in AMP kinase (AMPK) phosphorylation, AMPK activity, or phosphorylation of acetyl-CoA carboxylase in muscle and occurred despite increased expression of fatty acid transport protein 1. Palmitate oxidation was not significantly altered in MuPPARγKO mice despite the increased expression of several genes promoting lipid oxidation. These data demonstrate that PPARγ, even in the absence of exogenous activators, is required for normal rates of fatty acid uptake in oxidative skeletal muscle via mechanisms independent of AMPK and fatty acid transport protein 1. Thus, when PPARγ activity in muscle is absent or reduced, there will be decreased fatty acid disposal leading to diminished energy utilization and ultimately adiposity.

scholarly journals N-Acetylcysteine Inhibits Lipids Production in Mature Adipocytes through the Inhibition of Peroxisome Proliferator-Activated Receptor 

2020 ◽  
pp. 17-29
Author(s):  
Daniela Soto ◽  
Claudia Martini ◽  
Evelyn Frontera ◽  
Laura Montaldo ◽  
Maria C. Vila ◽  
...  
Keyword(s):  
In Vitro Study ◽  
Nutritional Supplement ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Peroxisome Proliferator Activated Receptor ◽  
Mrna And Protein Expression ◽  
Species Production ◽  
Lipids Production

Aims: Reports regarding the effects of antioxidants in obesity have been contradictory. Antioxidant N-acetylcysteine is usually considered a nutritional supplement. Our aim is to evaluate bioactivity of N-acetylcysteine (NAC) on mature adipocytes, which is a close model to in vivo condition. Study Design: In vitro study. Place and Duration of Study: Department of Basic Science (Universidad Nacional de Lujan), Department of Chemical Biology (Universidad de Buenos Aires), CONICET – INEDES and CONICET – IQUIBICEN, between March 2017 and June 2019. Methodology: We evaluated the bioactivity of different concentrations of NAC for 5 days (0.01 mM to 5 mM) on fully differentiated 3T3-L1 cells (mature adipocytes). Results: We demonstrated that NAC treatment was not toxic to mature adipocytes. Only 5mM NAC inhibited reactive oxygen species production. 5 mM NAC treatment resulted in a 60% decrease in cellular triglycerides content and inhibited 70% cholesterol accumulation.  We also determined the mRNA and protein expression levels of Peroxisome Proliferator-Activated Receptor g as well as, mRNA levels of lipid protein Perilipin in NAC treated adipocytes; we observed that 5mM NAC treatment caused nearly 30% decrease in the expression of these parameters. Conclusion: These results suggest that NAC could avoid lipid accumulation in mature adipocytes; the antioxidant NAC could be beneficial in obesity treatment.

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