Rosiglitazone Increases Indexes of Stearoyl-CoA Desaturase Activity in Humans: Link to Insulin Sensitization and the Role of Dominant-Negative Mutation in Peroxisome Proliferator-Activated Receptor-

Abstract Activation of the lipid-regulated nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) modifies the immunophenotype of monocyte-derived dendritic cells (DCs). However it has not been analyzed in a systematic manner how lipid metabolism and immune regulation are connected at the transcriptional level via this receptor. Here we present the genome-wide expression analyses of PPARγ-instructed human DCs. Receptor activation was achieved by exogenous, synthetic as well as endogenous, natural means. More than 1000 transcripts are regulated during DC development by activation of PPARγ; half of the changes are positive effects. These changes appear to enhance and modulate the robust gene expression alterations associated with monocyte to DC transition. Strikingly, only genes related to lipid metabolism are overrepresented among early induced genes. As a net consequence, lipid accumulation appears to be diminished in these cells. In contrast, genes related to immune response are regulated after 24 hours, implying the existence of indirect mechanisms of modulation. Receptor dependence was established by using DCs of patients harboring a dominant-negative mutation of PPARγ. Our data show that PPARγ acts as a mostly positive transcriptional regulator in human developing DCs, acting primarily through controlling genes involved in lipid metabolism and via this, indirectly modifying the immune phenotype.

Download Full-text

The role of the amino-terminal domain in the interaction of unliganded peroxisome proliferator-activated receptor γ-2 with nuclear receptor co-repressor

Journal of Molecular Endocrinology ◽

10.1677/jme-10-0007 ◽

2010 ◽

Vol 45 (3) ◽

pp. 133-145 ◽

Cited By ~ 9

Author(s):

Sadako Suzuki ◽

Shigekazu Sasaki ◽

Hiroshi Morita ◽

Yutaka Oki ◽

Daisuke Turiya ◽

...

Keyword(s):

Insulin Resistance ◽

Nuclear Receptor ◽

Thyroid Hormone Receptor ◽

Dominant Negative ◽

Peroxisome Proliferator ◽

Wild Type ◽

Peroxisome Proliferator Activated Receptor ◽

Amino Terminal

Peroxisome proliferator-activated receptor γ-2 (PPARG2) is a ligand-dependent transcriptional factor involved in the pathogenesis of insulin resistance. In the presence of a ligand, PPARG2 associates with co-activators, while it recruits co-repressors (CoRs) in the absence of a ligand. It has been reported that the interaction of liganded PPARG2 with co-activators is regulated by the amino-terminal A/B domain (NTD) via inter-domain communication. However, the role of the NTD is unknown in the case of the interaction between unliganded PPARG2 and CoRs. To elucidate this, total elimination of the influence of ligands is required, but the endogenous ligands of PPARG2 have not been fully defined. PPARG1-P467L, a naturally occurring mutant of PPARG1, was identified in a patient with severe insulin resistance. Reflecting its very low affinity for various ligands, this mutant does not have transcriptional activity in the PPAR response element, but exhibits dominant negative effects (DNEs) on liganded wild-type PPARG2-mediated transactivation. Using the corresponding PPARG2 mutant, PPARG2-P495L, we evaluated the role of the NTD in the interaction between unliganded PPARG2 and CoRs. Interestingly, the DNE of PPARG2-P495L was increased by the truncation of its NTD. NTD deletion also enhanced the DNE of a chimeric receptor, PT, in which the ligand-binding domain of PPARG2 was replaced with that of thyroid hormone receptor β-1. Moreover, NTD deletion facilitated the in vitro binding of nuclear receptor CoR with wild-type PPARG2, mutant P495L, and the PT chimera (PPARG2-THRB). Inter-domain communication in PPARG2 regulates not only ligand-dependent transactivation but also ligand-independent silencing.

Download Full-text

Abdominal subcutaneous adipose tissue morphology in a patient with a dominant-negative mutation (P467L) in the nuclear receptor peroxisome proliferator-activated receptor-gamma (PPARG) gene

Nutrition Metabolism and Cardiovascular Diseases ◽

10.1016/j.numecd.2009.10.018 ◽

2010 ◽

Vol 20 (3) ◽

pp. e11-e12 ◽

Cited By ~ 2

Author(s):

R. Boiani ◽

S. Cinti ◽

D.B. Savage ◽

A. Vidal-Puig ◽

S. O'Rahilly

Keyword(s):

Adipose Tissue ◽

Nuclear Receptor ◽

Subcutaneous Adipose Tissue ◽

Dominant Negative ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Tissue Morphology ◽

Dominant Negative Mutation ◽

Pparg Gene ◽

Subcutaneous Adipose

Download Full-text

Failure to vasodilate in response to salt loading blunts renal blood flow and causes salt-sensitive hypertension

Cardiovascular Research ◽

10.1093/cvr/cvaa147 ◽

2020 ◽

Cited By ~ 3

Author(s):

Jing Wu ◽

Larry N Agbor ◽

Shi Fang ◽

Masashi Mukohda ◽

Anand R Nair ◽

...

Keyword(s):

Blood Flow ◽

Smooth Muscle ◽

Renal Blood Flow ◽

Vascular Dysfunction ◽

Dominant Negative ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Salt Loading ◽

Dominant Negative Mutation ◽

Induced Hypertension

Abstract Aims Salt-sensitive (SS) hypertension is accompanied by impaired vasodilation in the systemic and renal circulation. However, the causal relationship between vascular dysfunction and salt-induced hypertension remains controversial. We sought to determine whether primary vascular dysfunction, characterized by a failure to vasodilate during salt loading, plays a causal role in the pathogenesis of SS hypertension. Methods and results Mice selectively expressing a peroxisome proliferator-activated receptor γ dominant-negative mutation in vascular smooth muscle (S-P467L) exhibited progressive SS hypertension during a 4 week high salt diet (HSD). This was associated with severely impaired vasodilation in systemic and renal vessels. Salt-induced impairment of vasodilation occurred as early as 3 days after HSD, which preceded the onset of SS hypertension. Notably, the overt salt-induced hypertension in S-P467L mice was not driven by higher cardiac output, implying elevations in peripheral vascular resistance. In keeping with this, HSD-fed S-P467L mice exhibited decreased smooth muscle responsiveness to nitric oxide (NO) in systemic vessels. HSD-fed S-P467L mice also exhibited elevated albuminuria and a blunted increase in urinary NO metabolites which was associated with blunted renal blood flow and increased sodium retention mediated by a lack of HSD-induced suppression of NKCC2. Blocking NKCC2 function prevented the salt-induced increase in blood pressure in S-P467L mice. Conclusion We conclude that failure to vasodilate in response to salt loading causes SS hypertension by restricting renal perfusion and reducing renal NO through a mechanism involving NKCC2 in a mouse model of vascular peroxisome proliferator-activated receptor γ impairment.

Download Full-text

Conditional Expression of Human PPARδand a Dominant Negative Variant of hPPARδ In Vivo

PPAR Research ◽

10.1155/2012/216817 ◽

2012 ◽

Vol 2012 ◽

pp. 1-12 ◽

Cited By ~ 2

Author(s):

Larry G. Higgins ◽

Wojciech G. Garbacz ◽

Mattias C. U. Gustafsson ◽

Sitheswaran Nainamalai ◽

Peter R. Ashby ◽

...

Keyword(s):

Target Genes ◽

Dominant Negative ◽

Peroxisome Proliferator ◽

Placental Development ◽

Peroxisome Proliferator Activated Receptor ◽

Conditional Expression ◽

Dominant Negative Variant ◽

First Time

The nuclear receptor, NR1C2 or peroxisome proliferator-activated receptor (PPAR)-δ, is ubiquitously expressed and important for placental development, fatty acid metabolism, wound healing, inflammation, and tumour development. PPARδhas been hypothesized to function as both a ligand activated transcription factor and a repressor of transcription in the absence of agonist. In this paper, treatment of mice conditionally expressing human PPARδwith GW501516 resulted in a marked loss in body weight that was not evident in nontransgenic animals or animals expressing a dominant negative derivative of PPARδ. Expression of either functional or dominant negative hPPARδblocked bezafibrate-induced PPARα-dependent hepatomegaly and blocked the effect of bezafibrate on the transcription of PPARαtarget genes. These data demonstrate, for the first time, that PPARδcould inhibit the activation of PPARα in vivoand provide novel models for the investigation of the role of PPARδin pathophysiology.

Download Full-text

Peroxisome proliferator-activated receptor-γ protects against vascular aging

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00557.2011 ◽

2012 ◽

Vol 302 (10) ◽

pp. R1184-R1190 ◽

Cited By ~ 17

Author(s):

Mary L. Modrick ◽

Dale A. Kinzenbaw ◽

Yi Chu ◽

Curt D. Sigmund ◽

Frank M. Faraci

Keyword(s):

Endothelial Dysfunction ◽

Vascular Disease ◽

Protective Role ◽

Dominant Negative ◽

Peroxisome Proliferator ◽

Vascular Aging ◽

Wild Type ◽

No Donor ◽

Peroxisome Proliferator Activated Receptor ◽

Dominant Negative Mutation

Vascular disease occurs commonly during aging. Carotid artery and cerebrovascular disease are major causes of stroke and contributors to dementia. Recent evidence suggests that peroxisome proliferator-activated receptor-γ (PPARγ) may play a protective role in the vasculature, but the potential importance of PPARγ in vascular aging is unknown. To examine the hypothesis that PPARγ normally protects against vascular aging, we studied heterozygous knockin mice expressing a human dominant-negative mutation in PPARγ (P465L, designated L/+). Endothelial dysfunction, a major contributor to vascular disease, was studied using carotid arteries from adult (8 ± 1 mo) and old (24 ± 1 mo) L/+ mice and wild-type littermates. In arteries from wild-type mice, responses to the endothelium-dependent agonist ACh were similar in adult and old wild-type mice but were reduced by ∼50% in old L/+ mice ( n = 7–10, P < 0.05). Impaired responses in arteries from old L/+ mice were restored to normal by a scavenger of superoxide. Relaxation of arteries to nitroprusside (an NO donor) was similar in all groups. Contraction of arteries to U46619 was not affected by age or genotype, while maximal responses to endothelin-1 were reduced with age in both wild-type and L/+ mice. Vascular expression (mRNA) of the catalytic component of NADPH oxidase (Nox2) was not altered in wild-type mice but was increased significantly in old L/+ mice. These findings provide the first evidence that interference with PPARγ function accelerates vascular aging, suggesting a novel role for PPARγ in protecting against age-induced oxidative stress and endothelial dysfunction.

Download Full-text

The emerging role of COX-2, 15-LOX, and PPARγ in metabolic diseases and cancer: An introduction to novel multi-target directed ligands (MTDLs)

Current Medicinal Chemistry ◽

10.2174/0929867327999200820173853 ◽

2020 ◽

Vol 27 ◽

Cited By ~ 1

Author(s):

Rana A. Alaaeddine ◽

Perihan A. Elzahhar ◽

Ibrahim AlZaim ◽

Wassim Abou-Kheir ◽

Ahmed S.F. Belal ◽

...

Keyword(s):

Metabolic Diseases ◽

Biological Effects ◽

Arachidonic Acid Metabolism ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Cellular Targets ◽

Design And Synthesis ◽

Early Results ◽

Cox 2

: Emerging evidence supports an intertwining framework for the involvement of different inflammatory pathways in a common pathological background for a number of disorders. Of importance are pathways involving arachidonic acid metabolism by cyclooxygenase-2 (COX-2) and 15-lipoxygenase (15-LOX). Both enzyme activities and their products are implicated in a range of pathophysiological processes encompassing metabolic impairment leading to adipose inflammation and the subsequent vascular and neurological disorders, in addition to various pro-and anti-tumorigenic effects. A further layer of complexity is encountered by the disparate, and often reciprocal, modulatory effect COX-2 and 15-LOX activities and metabolites exert on each other or on other cellular targets, the most prominent of which is peroxisome proliferator-activated receptor gamma (PPARγ). Thus, effective therapeutic intervention with such multifaceted disorders requires the simultaneous modulation of more than one target. Here, we describe the role of COX-2, 15-LOX, and PPARγ in cancer and complications of metabolic disorders, highlight the value of designing multi-target directed ligands (MTDLs) modifying their activity, and summarize the available literature regarding the rationale and feasibility of design and synthesis of these ligands together with their known biological effects. We speculate on the potential impact of MTDLs in these disorders as well as emphasize the need for structured future effort to translate these early results facilitating the adoption of these, and similar, molecules in clinical research.

Download Full-text

The Nutraceutical N-Palmitoylethanolamide (PEA) Reveals Widespread Molecular Effects Unmasking New Therapeutic Targets in Murine Varicocele

Nutrients ◽

10.3390/nu13030734 ◽

2021 ◽

Vol 13 (3) ◽

pp. 734

Author(s):

Pietro Antonuccio ◽

Herbert Ryan Marini ◽

Antonio Micali ◽

Carmelo Romeo ◽

Roberta Granese ◽

...

Keyword(s):

Transforming Growth Factor ◽

Therapeutic Targets ◽

Sham Operation ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Pyrin Domain ◽

Age Related ◽

Extracellular Signal ◽

Morphometric Assessment

Varicocele is an age-related disease with no current medical treatments positively impacting infertility. Toll-like receptor 4 (TLR4) expression is present in normal testis with an involvement in the immunological reactions. The role of peroxisome proliferator-activated receptor-α (PPAR-α), a nuclear receptor, in fertility is still unclear. N-Palmitoylethanolamide (PEA), an emerging nutraceutical compound present in plants and animal foods, is an endogenous PPAR-α agonist with well-demonstrated anti-inflammatory and analgesics characteristics. In this model of mice varicocele, PPAR-α and TLR4 receptors’ roles were investigated through the administration of ultra-micronized PEA (PEA-um). Male wild-type (WT), PPAR-α knockout (KO), and TLR4 KO mice were used. A group underwent sham operation and administration of vehicle or PEA-um (10 mg/kg i.p.) for 21 days. Another group (WT, PPAR-α KO, and TLR4 KO) underwent surgical varicocele and was treated with vehicle or PEA-um (10 mg/kg i.p.) for 21 days. At the end of treatments, all animals were euthanized. Both operated and contralateral testes were processed for histological and morphometric assessment, for PPAR-α, TLR4, occludin, and claudin-11 immunohistochemistry and for PPAR-α, TLR4, transforming growth factor-beta3 (TGF-β3), phospho-extracellular signal-Regulated-Kinase (p-ERK) 1/2, and nucleotide-binding oligomerization domain-like receptor (NLR) family pyrin domain-containing 3 (NLRP3) Western blot analysis. Collectively, our data showed that administration of PEA-um revealed a key role of PPAR-α and TLR4 in varicocele pathophysiology, unmasking new nutraceutical therapeutic targets for future varicocele research and supporting surgical management of male infertility.

Download Full-text

From Exercise to Cognitive Performance: Role of Irisin

Applied Sciences ◽

10.3390/app11157120 ◽

2021 ◽

Vol 11 (15) ◽

pp. 7120

Author(s):

Mirko Pesce ◽

Irene La Fratta ◽

Teresa Paolucci ◽

Alfredo Grilli ◽

Antonia Patruno ◽

...

Keyword(s):

The Elderly ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Beneficial Effects ◽

General Exercise ◽

Fibronectin Type Iii ◽

Exercise Induced ◽

Fibronectin Type Iii Domain ◽

The Brain

The beneficial effects of exercise on the brain are well known. In general, exercise offers an effective way to improve cognitive function in all ages, particularly in the elderly, who are considered the most vulnerable to neurodegenerative disorders. In this regard, myokines, hormones secreted by muscle in response to exercise, have recently gained attention as beneficial mediators. Irisin is a novel exercise-induced myokine, that modulates several bodily processes, such as glucose homeostasis, and reduces systemic inflammation. Irisin is cleaved from fibronectin type III domain containing 5 (FNDC5), a transmembrane precursor protein expressed in muscle under the control of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α). The FNDC5/irisin system is also expressed in the hippocampus, where it stimulates the expression of the neurotrophin brain-derived neurotrophic factor in this area that is associated with learning and memory. In this review, we aimed to discuss the role of irisin as a key mediator of the beneficial effects of exercise on synaptic plasticity and memory in the elderly, suggesting its roles within the main promoters of the beneficial effects of exercise on the brain.

Download Full-text

The Novel Role of PGC1α in Bone Metabolism

International Journal of Molecular Sciences ◽

10.3390/ijms22094670 ◽

2021 ◽

Vol 22 (9) ◽

pp. 4670

Author(s):

Cinzia Buccoliero ◽

Manuela Dicarlo ◽

Patrizia Pignataro ◽

Francesco Gaccione ◽

Silvia Colucci ◽

...

Keyword(s):

Bone Metabolism ◽

Osteoblastic Differentiation ◽

In Vivo Studies ◽

Peroxisome Proliferator ◽

Sirtuin 3 ◽

Peroxisome Proliferator Activated Receptor ◽

Increased Risk

Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) is a protein that promotes transcription of numerous genes, particularly those responsible for the regulation of mitochondrial biogenesis. Evidence for a key role of PGC1α in bone metabolism is very recent. In vivo studies showed that PGC1α deletion negatively affects cortical thickness, trabecular organization and resistance to flexion, resulting in increased risk of fracture. Furthermore, in a mouse model of bone disease, PGC1α activation stimulates osteoblastic gene expression and inhibits atrogene transcription. PGC1α overexpression positively affects the activity of Sirtuin 3, a mitochondrial nicotinammide adenina dinucleotide (NAD)-dependent deacetylase, on osteoblastic differentiation. In vitro, PGC1α overexpression prevents the reduction of mitochondrial density, membrane potential and alkaline phosphatase activity caused by Sirtuin 3 knockdown in osteoblasts. Moreover, PGC1α influences the commitment of skeletal stem cells towards an osteogenic lineage, while negatively affects marrow adipose tissue accumulation. In this review, we will focus on recent findings about PGC1α action on bone metabolism, in vivo and in vitro, and in pathologies that cause bone loss, such as osteoporosis and type 2 diabetes.

Download Full-text