scholarly journals Peroxisomal Multifunctional Protein 2 Is Essential for Lipid Homeostasis in Sertoli Cells and Male Fertility in Mice

Endocrinology ◽  
2006 ◽  
Vol 147 (5) ◽  
pp. 2228-2236 ◽  
Author(s):  
Steven Huyghe ◽  
Henning Schmalbruch ◽  
Karel De Gendt ◽  
Guido Verhoeven ◽  
Florian Guillou ◽  
...  
Keyword(s):  
Germ Cells ◽  
Sertoli Cells ◽  
Male Fertility ◽  
Neutral Lipids ◽  
Docosapentaenoic Acid ◽  
Testicular Atrophy ◽  
Lipid Homeostasis ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Multifunctional Protein

Inactivation of peroxisomal β-oxidation in mice, by knocking out multifunctional protein-2 (MFP-2; also called d-bifunctional enzyme), causes male infertility. In the testis, extensive accumulations of neutral lipids were observed in Sertoli cells, beginning in prepubertal mice and evolving in complete testicular atrophy by the age of 4 months. Spermatogenesis was already severely affected at the age of 5 wk, and pre- and postmeiotic germ cells gradually disappeared from the tubuli seminiferi. Based on cytochemical stainings and biochemical analyses, the lipid droplets consisted of cholesteryl esters and neutral glycerolipids. Furthermore, peroxisomal β-oxidation substrates, such as very-long-chain fatty acids and pristanic acid, accumulated in the testis, whereas the concentration of docosapentaenoic acid, a polyunsaturated fatty acid and peroxisomal β-oxidation product, was reduced. The testicular defects were also present in double MFP-2/peroxisome proliferator-activated receptor-α knockout mice, ruling out the possibility that they were mediated through the activation of this nuclear receptor. Immunoreactivity for peroxisomal proteins, including MFP-2, was detected in Sertoli cells as well as in germ cells and Leydig cells. The pivotal role of peroxisomal metabolism in Sertoli cells was also demonstrated by generating mice with a Sertoli cell-selective elimination of peroxisomes through cell type-specific inactivation of the peroxin 5 gene. These mice also developed lipid inclusions and were infertile, and their testes fully degenerated by the age of 4 months. In conclusion, the present data demonstrate that peroxisomal β-oxidation is essential for lipid homeostasis in the testis and for male fertility.

scholarly journals Smad2/3 Upregulates the Expression of Vimentin and Affects Its Distribution in DBP-Exposed Sertoli Cells

PPAR Research ◽  
2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
Xi Zhang ◽  
Xiaogang Wang ◽  
Taixiu Liu ◽  
Min Mo ◽  
Lin Ao ◽  
...  
Keyword(s):  
Real Time ◽  
Germ Cells ◽  
Cross Talk ◽  
Sertoli Cells ◽  
Real Time Pcr ◽  
Nutritional Support ◽  
Dibutyl Phthalate ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor

Sertoli cells (SCs) in the testes provide physical and nutritional support to germ cells. The vimentin cytoskeleton in SCs is disrupted by dibutyl phthalate (DBP), which leads to SCs dysfunction. In a previous study, we found that peroxisome proliferator-activated receptor alpha (PPARα) influenced the distribution of vimentin by affecting its phosphorylation in DBP-exposed SCs. In the present study, we investigated the role of Smad2/3 in regulating the expression of vimentin in DBP-exposed SCs. We hypothesized that Smad2/3 affects the distribution of vimentin by regulating its expression and that there is cross talk between Smad2/3 and PPARα. The real-time PCR and ChIP-qPCR results showed that SB431542 (an inhibitor of Smad2/3) could significantly attenuate the expression of vimentin induced by DBP in SCs. Phosphorylated and soluble vimentin were both downregulated by SB431542 pretreatment. WY14643 (an agonist of PPARα) pretreatment stimulated, while GW6471 (an antagonist of PPARα) inhibited, the activity of Smad2/3; SB431542 pretreatment also inhibited the activity of PPARα, but it did not rescue the DBP-induced collapse in vimentin. Our results suggest that, in addition to promoting the phosphorylation of vimentin, DBP also stimulates the expression of vimentin by activating Smad2/3 in SCs and thereby induces irregular vimentin distribution.

scholarly journals Peroxisome Proliferator-activated Receptor-α Regulates Lipid Homeostasis, but Is Not Associated with Obesity

2001 ◽  
Vol 276 (42) ◽  
pp. 39088-39093 ◽  
Author(s):  
Taro E. Akiyama ◽  
Christopher J. Nicol ◽  
Catherine Fievet ◽  
Bart Staels ◽  
Jerrold M. Ward ◽  
...  
Keyword(s):  
Lipid Homeostasis ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor

15-Deoxy-Δ12,14-prostaglandin J2 and peroxisome proliferator-activated receptor γ (PPARγ) levels in term placental tissues from control and diabetic rats: modulatory effects of a PPARγ agonist on nitridergic and lipid placental metabolism

2005 ◽  
Vol 17 (4) ◽  
pp. 423 ◽  
Author(s):  
E. Capobianco ◽  
A. Jawerbaum ◽  
M. C. Romanini ◽  
V. White ◽  
C. Pustovrh ◽  
...  
Keyword(s):  
De Novo ◽  
Lipid Synthesis ◽  
Diabetic Rats ◽  
Lipid Homeostasis ◽  
Diabetic Rat ◽  
No Production ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Pparγ Agonist ◽  
Prostaglandin J2

15-Deoxy-Δ12,14-prostaglandin J2 (15dPGJ2) is a peroxisome proliferator-activated receptor γ (PPARγ) ligand that regulates lipid homeostasis and has anti-inflammatory properties in many cell types. We postulated that 15dPGJ2 may regulate lipid homeostasis and nitric oxide (NO) levels in term placental tissues and that alterations in these pathways may be involved in diabetes-induced placental derangements. In the present study, we observed that, in term placental tissues from streptozotocin-induced diabetic rats, 15dPGJ2 concentrations were decreased (83%) and immunostaining for nitrotyrosine, indicating peroxynitrite-induced damage, was increased. In the presence of 15dPGJ2, concentrations of nitrates/nitrites (an index of NO production) were diminished (40%) in both control and diabetic rats, an effect that seems to be both dependent on and independent of PPARγ activation. Exogenous 15dPGJ2 did not modify lipid mass, but decreased the incorporation of 14C-acetate into triacylglycerol (35%), cholesteryl ester (55%) and phospholipid (32%) in placenta from control rats, an effect that appears to be dependent on PPARγ activation. In contrast, the addition of 15dPGJ2 did not alter de novo lipid synthesis in diabetic rat placenta, which showed decreased levels of PPARγ. We conclude that 15dPGJ2 modulates placental lipid metabolism and NO production. The concentration and function of 15dPGJ2 and concentrations of PPARγ were altered in placentas from diabetic rats, anomalies probably involved in diabetes-induced placental dysfunction.

scholarly journals Peroxisome Proliferator-Activated Receptor Delta: A Conserved Director of Lipid Homeostasis through Regulation of the Oxidative Capacity of Muscle

PPAR Research ◽  
2008 ◽  
Vol 2008 ◽  
pp. 1-7 ◽  
Author(s):  
Pieter de Lange ◽  
Assunta Lombardi ◽  
Elena Silvestri ◽  
Fernando Goglia ◽  
Antonia Lanni ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acids ◽  
Oxidative Capacity ◽  
Whole Body ◽  
Lipid Homeostasis ◽  
Peroxisome Proliferator ◽  
Transcriptional Program ◽  
Peroxisome Proliferator Activated Receptor ◽  
Peroxisome Proliferator Activated Receptors ◽  
Metabolic Action

The peroxisome proliferator-activated receptors (PPARs), which are ligand-inducible transcription factors expressed in a variety of tissues, have been shown to perform key roles in lipid homeostasis. In physiological situations such as fasting and physical exercise, one PPAR subtype, PPARδ, triggers a transcriptional program in skeletal muscle leading to a switch in fuel usage from glucose/fatty acids to solely fatty acids, thereby drastically increasing its oxidative capacity. The metabolic action of PPARδ has also been verified in humans. In addition, it has become clear that the action of PPARδ is not restricted to skeletal muscle. Indeed, PPARδ has been shown to play a crucial role in whole-body lipid homeostasis as well as in insulin sensitivity, and it is active not only in skeletal muscle (as an activator of fat burning) but also in the liver (where it can activate glycolysis/lipogenesis, with the produced fat being oxidized in muscle) and in the adipose tissue (by incrementing lipolysis). The main aim of this review is to highlight the central role for activated PPARδ in the reversal of any tendency toward the development of insulin resistance.

scholarly journals The Transcriptional Response to a Peroxisome Proliferator-activated Receptor α Agonist Includes Increased Expression of Proteome Maintenance Genes

2004 ◽  
Vol 279 (50) ◽  
pp. 52390-52398 ◽  
Author(s):  
Steven P. Anderson ◽  
Paul Howroyd ◽  
Jie Liu ◽  
Xun Qian ◽  
Rainer Bahnemann ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Stress Responses ◽  
Transcriptional Response ◽  
Lipid Homeostasis ◽  
Peroxisome Proliferator ◽  
Wild Type ◽  
Peroxisome Proliferator Activated Receptor ◽  
Proteasomal Genes ◽  
Oxidative Stress Responses

The nuclear receptor peroxisome proliferator-activated receptor α (PPARα), in addition to regulating lipid homeostasis, controls the level of tissue damage after chemical or physical stress. To determine the role of PPARα in oxidative stress responses, we examined damage after exposure to chemicals that increase oxidative stress in wild-type or PPARα-null mice. Primary hepatocytes from wild-type but not PPARα-null mice pretreated with the PPAR pan-agonist WY-14,643 (WY) were protected from damage to cadmium and paraquat. The livers from intact wild-type but not PPARα-null mice were more resistant to damage after carbon tetrachloride treatment. To determine the molecular basis of the protection by PPARα, we identified by transcript profiling genes whose expression was altered by a 7-day exposure to WY in wild-type and PPARα-null mice. Of the 815 genes regulated by WY in wild-type mice (p≤ 0.001; ≥1.5-fold or ≤-1.5-fold), only two genes were regulated similarly by WY in PPARα-null mice. WY increased expression of stress modifier genes that maintain the health of the proteome, including those that prevent protein aggregation (heat stress-inducible chaperones) and eliminate damaged proteins (proteasome components). Although the induction of proteasomal genes significantly overlapped with those regulated by 1,2-dithiole-3-thione, an activator of oxidant-inducible Nrf2, WY increased expression of proteasomal genes independently of Nrf2. Thus, PPARα controls the vast majority of gene expression changes after exposure to WY in the mouse liver and protects the liver from oxidant-induced damage, possibly through regulation of a distinct set of proteome maintenance genes.

scholarly journals 3D-PHARMACOPHORE MODELLING OF OMEGA-3 DERIVATIVES WITH PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR GAMMA AS AN ANTI-OBESITY AGENT

2021 ◽  
pp. 167-170
Author(s):  
IDA MUSFIROH ◽  
GINNA MEGAWATI ◽  
DEWI MARHENI DIAH HERAWATI ◽  
AGUS RUSDIN
Keyword(s):  
Functional Groups ◽  
Complex Structure ◽  
Pharmacophore Model ◽  
Docosapentaenoic Acid ◽  
Peroxisome Proliferator ◽  
Omega 3 ◽  
Peroxisome Proliferator Activated Receptor ◽  
Pharmacophore Modelling ◽  
Ppar Γ ◽  
3D Pharmacophore

Objective: The aim of this work was to study the pharmacophore model of omega-3 derivatives with the PPAR-γ receptor using LigandScout 4.4.3 to investigate the important chemical interactions of complex structure. Methods: The methods consisted of structure preparation of nine chemical compounds derived from omega-3 fatty acids, database preparation, creating 3D Pharmacophore modelling, validation pharmacophore, and screening test compounds. Results: The result of the research showed that the omega-3 derivatives docosahexaenoic acid (DHA), when eicosapentaenoic acid (HPA), and docosapentaenoic acid (DPA) have the best pharmacophore fit values of 36.59; 36.56; and 36.56, respectively. According to the results of the pharmacophore study, the carbonyl and hydroxyl of the carboxylate functional groups become the active functional groups that exhibit hydrogen bonding interactions. While the alkyl chain (Ethyl and methyl groups) was the portion that can be modified to increase its activity. Conclusion: Omega-3 derivatives could be used as a lead drug for the powerful PPAR-γ receptor in the prevention and treatment of obesity.

scholarly journals PPARs as Metabolic Regulators in the Liver: Lessons from Liver-Specific PPAR-Null Mice

2020 ◽  
Vol 21 (6) ◽  
pp. 2061 ◽  
Author(s):  
Yaping Wang ◽  
Takero Nakajima ◽  
Frank J. Gonzalez ◽  
Naoki Tanaka
Keyword(s):  
Fatty Acid ◽  
Lipid Metabolism ◽  
Liver Cancer ◽  
Energy Homeostasis ◽  
Whole Body ◽  
Lipid Homeostasis ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Metabolic Regulators

Peroxisome proliferator-activated receptor (PPAR) α, β/δ, and γ modulate lipid homeostasis. PPARα regulates lipid metabolism in the liver, the organ that largely controls whole-body nutrient/energy homeostasis, and its abnormalities may lead to hepatic steatosis, steatohepatitis, steatofibrosis, and liver cancer. PPARβ/δ promotes fatty acid β-oxidation largely in extrahepatic organs, and PPARγ stores triacylglycerol in adipocytes. Investigations using liver-specific PPAR-disrupted mice have revealed major but distinct contributions of the three PPARs in the liver. This review summarizes the findings of liver-specific PPAR-null mice and discusses the role of PPARs in the liver.

scholarly journals Inhibition of the Lipid Droplet–Peroxisome Proliferator-Activated Receptor α Axis Suppresses Cancer Stem Cell Properties

Genes ◽  
2021 ◽  
Vol 12 (1) ◽  
pp. 99
Author(s):  
Kenta Kuramoto ◽  
Masahiro Yamamoto ◽  
Shuhei Suzuki ◽  
Keita Togashi ◽  
Tomomi Sanomachi ◽  
...  
Keyword(s):  
Energy Source ◽  
Signal Transduction ◽  
Lipid Droplets ◽  
Neutral Lipids ◽  
Peroxisome Proliferator ◽  
Cancer Stemness ◽  
Self Renewal ◽  
Peroxisome Proliferator Activated Receptor ◽  
Endogenous Lipid ◽  
Ppar Signaling

Cancer stem cells (CSCs), having both self-renewal and tumorigenic capacity, utilize an energy metabolism system different from that of non-CSCs. Lipid droplets (LDs) are organelles that store neutral lipids, including triacylglycerol. Previous studies demonstrated that LDs are formed and store lipids as an energy source in some CSCs. LDs play central roles not only in lipid storage, but also as a source of endogenous lipid ligands, which are involved in numerous signaling pathways, including the peroxisome proliferator-activated receptor (PPAR) signaling pathway. However, it remains unclear whether LD-derived signal transduction is involved in the maintenance of the properties of CSCs. We investigated the roles of LDs in cancer stemness using pancreatic and colorectal CSCs and isogenic non-CSCs. PPARα was activated in CSCs in which LDs accumulated, but not in non-CSCs, and pharmacological and genetic inhibition of PPARα suppressed cancer stemness. In addition, inhibition of both re-esterification and lipolysis pathways suppressed cancer stemness. Our study suggested that LD metabolic turnover accompanying PPARα activation is a promising anti-CSC therapeutic target.

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