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.

Abstract 290: Proliferation of Cardiac Fibroblasts Defines Early Stages of Genetic Dilated Cardiomyopathy and Precedes Myocardial Metabolic Derangement

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Michael A Burke ◽  
Stephen Chang ◽  
Danos C Christodoulou ◽  
Joshua M Gorham ◽  
Hiroko Wakimoto ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cardiac Fibroblasts ◽  
Expression Patterns ◽  
Molecular Networks ◽  
Peroxisome Proliferator ◽  
Metabolic Derangement ◽  
Peroxisome Proliferator Activated Receptor ◽  
Cell Remodeling ◽  
Ppar Signaling ◽  
Myocyte Proliferation

The complex molecular networks underpinning DCM remain poorly understood. To study distinct pathways and networks in the longitudinal development of DCM we performed RNAseq on LV tissue from mice carrying a human DCM mutation in phospholamban (PLN R9C/+ ) before phenotype onset (pre-DCM), with DCM, and during overt heart failure (HF), and also on isolated myocytes and non-myocytes from DCM hearts. PLN R9C/+ mice show progressive fibrosis (20% vs. 1% control, p=6x10 −33 ; n=3) associated with proliferation of cardiac non-myocytes (33% increase over control, p=6x10 −4 ; n=3). Consistent with this, cardiac non-myocytes have upregulated gene expression and pathways, while these are generally downregulated in myocytes. Non-myocytes were enriched in fibrosis, inflammation, and cell remodeling pathways, from pre-DCM to HF. In contrast, myocytes were enriched for metabolic pathways only with overt DCM and HF. Myocytes showed profound derangement of oxidative phosphorylation with DCM (p=2.5x10 −41 ; 44% (53/120) of pathway genes downregulated), suggesting mitochondrial dysfunction. Additionally, we detected probable inhibition of peroxisome proliferator-activated receptor (PPAR) signaling by diminished expression of pathway genes (Figure). DCM and hypertrophic remodeling was compared using RNAseq of a mouse model of HCM; similar patterns of fibrosis with myocyte metabolic dysregulation were evident despite unique differential gene expression patterns between models. DCM caused by PLN R9C/+ is associated with early non-myocyte proliferation and later myocyte metabolic derangement possibly governed by altered PPAR signaling, and is common to DCM and HCM.

scholarly journals Circadian Gene PER2 Silencing Downregulates PPARG and SREBF1 and Suppresses Lipid Synthesis in Bovine Mammary Epithelial Cells

Biology ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 1226
Author(s):  
Yujia Jing ◽  
Yifei Chen ◽  
Shan Wang ◽  
Jialiang Ouyang ◽  
Liangyu Hu ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Epithelial Cells ◽  
Circadian Clock ◽  
Lipid Droplets ◽  
Mammary Epithelial Cells ◽  
Lipid Synthesis ◽  
Mammary Epithelial ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Bovine Mammary Epithelial Cells

PER2, a circadian clock gene, is associated with mammary gland development and lipid synthesis in rodents, partly via regulating peroxisome proliferator-activated receptor gamma (PPARG). Whether such a type of molecular link existed in bovines was unclear. We hypothesized that PER2 was associated with lipid metabolism and regulated cell cycles and apoptosis in bovine mammary epithelial cells (BMECs). To test this hypothesis, BMECs isolated from three mid-lactation (average 110 d postpartum) cows were used. The transient transfection of small interfering RNA (siRNA) was used to inhibit PER2 transcription in primary BMECs. The silencing of PER2 led to lower concentrations of cellular lipid droplets and triacylglycerol along with the downregulation of lipogenic-related genes such as ACACA, FASN, LPIN1, and SCD, suggesting an overall inhibition of lipogenesis and desaturation. The downregulation of PPARG and SREBF1 in response to PER2 silencing underscored the importance of circadian clock signaling and the transcriptional regulation of lipogenesis. Although the proliferation of BMECs was not influenced by PER2 silencing, the number of cells in the G2/GM phase was upregulated. PER2 silencing did not affect cell apoptosis. Overall, the data provided evidence that PER2 participated in the coordination of mammary lipid metabolism and was potentially a component of the control of lipid droplets and TAG synthesis in ruminant mammary cells. The present data suggested that such an effect could occur through direct effects on transcriptional regulators.

scholarly journals Genetic variants of the peroxisome proliferator‐activated receptor (PPAR) signaling pathway genes and risk of pancreatic cancer

2020 ◽  
Vol 59 (8) ◽  
pp. 930-939
Author(s):  
Xiaowen Liu ◽  
Danwen Qian ◽  
Hongliang Liu ◽  
James L. Abbruzzese ◽  
Sheng Luo ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Signaling Pathway ◽  
Genetic Variants ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Signaling

scholarly journals DEF-1, a Novel Src SH3 Binding Protein That Promotes Adipogenesis in Fibroblastic Cell Lines

1999 ◽  
Vol 19 (3) ◽  
pp. 2330-2337 ◽  
Author(s):  
Frederick J. King ◽  
Erding Hu ◽  
David F. Harris ◽  
Pasha Sarraf ◽  
Bruce M. Spiegelman ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Ectopic Expression ◽  
Signal Transduction Pathway ◽  
Bovine Brain ◽  
Cellular Growth ◽  
Affinity Column ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Efficient Induction ◽  
Signal Transduction Proteins

ABSTRACT The Src homology 3 (SH3) motif is found in numerous signal transduction proteins involved in cellular growth and differentiation. We have purified and cloned a novel protein, DEF-1 (differentiation-enhancing factor), from bovine brain by using a Src SH3 affinity column. Ectopic expression of DEF-1 in fibroblasts resulted in the differentiation of a significant fraction of the culture into adipocytes. This phenotype appears to be related to the induction of the transcription factor peroxisome proliferator-activated receptor γ (PPARγ), since DEF-1 NIH 3T3 cells demonstrated augmented levels of PPARγ mRNA and, when treated with activating PPARγ ligands, efficient induction of differentiation. Further evidence for a role for DEF-1 in adipogenesis was provided by heightened expression of DEF-1 mRNA in adipose tissue isolated fromobese and diabetes mice compared to that in tissue isolated from wild-type mice. However, DEF-1 mRNA was detected in multiple tissues, suggesting that the signal transduction pathway(s) in which DEF-1 is involved is not limited to adipogenesis. These results suggest that DEF-1 is an important component of a signal transduction process that is involved in the differentiation of fibroblasts and possibly of other types of cells.

Molecular mechanisms of signal transduction via adiponectin and adiponectin receptors

2010 ◽  
Vol 391 (9) ◽  
Author(s):  
John T. Heiker ◽  
David Kosel ◽  
Annette G. Beck-Sickinger
Keyword(s):  
Signal Transduction ◽  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Molecular Characteristics ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Downstream Signaling ◽  
Specific Effects ◽  
Intracellular Binding ◽  
Functional Mechanisms

Abstract The adipocytokine adiponectin and its receptor (AdipoR) comprise a new receptor-ligand system that is involved in a variety of clinically important morbidities such as obesity, type 2 diabetes and cardiovascular diseases. Adiponectin exerts a multitude of beneficial and tissue specific effects depending on its unique, tightly regulated multimerization behavior. Post-translational modifications are essential for the multimer assembly before secretion and protein stability in the circulation. AdipoR1 and 2 have been discovered as a new class of heptahelix receptors structurally and functionally distinct from G-protein-coupled receptors. Both AdipoRs bind adiponectin and the downstream signaling of both AdipoRs is mediated mainly by phosphorylation of AMPK and activation of peroxisome proliferator-activated receptor α, which influence the lipid and glucose metabolism of skeletal muscle and liver cells as well as inflammatory processes and vascular endothelial integrity. Several intracellular binding partners of the AdipoR N-terminus such as APPL1, CK2β and ERp46 have been identified and shown to control receptor signaling. Adiponectin has also been reported to modulate the dimerization and internalization of AdipoRs, which provides new insights into the molecular characteristics of this unusual receptor. The understanding of the functional mechanisms of adiponectin signal transduction is critical to benefit from the full therapeutic potential of the adiponectin-AdipoR system.

scholarly journals Effect of Gender to Fat Deposition in Yaks Based on Transcriptomic and Metabolomics Analysis

2021 ◽  
Vol 9 ◽  
Author(s):  
Lin Xiong ◽  
Jie Pei ◽  
Xiaoyun Wu ◽  
Qudratullah Kalwar ◽  
Ping Yan ◽  
...  
Keyword(s):  
Meat Quality ◽  
Subcutaneous Fat ◽  
Focal Adhesions ◽  
Tca Cycle ◽  
Fat Deposition ◽  
Receptor Interaction ◽  
Peroxisome Proliferator ◽  
Steroid Synthesis ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Signaling

Fat deposition in yaks plays an important part in survival, multiplication, and meat quality. In this work, the characteristic of fat deposition in male yaks (MYs) and female yaks (FYs) and the regulations of gender to yak fat deposition were explored by mRNA-Seq and non-targeted metabolomics analyses. FYs possessed a higher body fat rate (BFR) of visceral fat, fat content in longissimus dorsi (LD) and liver, and subcutaneous fat thickness (p < 0.05). The fat and cholesterol synthesis in liver and the fat transport in FY blood increased. The fat metabolism in yaks is the combined effect of carbohydrate, fatty acid, and amino acid metabolism by tricarboxylic acid (TCA) cycle, and an increase of triglyceride (TG) synthesis was accompanied by an increase of steroid synthesis. The high levels of myo-inositol and cortisol (COR) (p < 0.01) activated the calcium signaling in FY subcutaneous fat, followed by the increase of adipocyte secretion, and resulted in more leptin (LEP) secretion (p < 0.01). Then peroxisome proliferator-activated receptor (PPAR) signaling was activated by the focal adhesions and ECM–receptor interaction. Finally, the TG and steroid synthesis increased by the expression regulation of ME1, SCD, ELOVL6, DGAT2, DBI, LPL, CPT1, PLIN1, LIPA, DHCR24, and SQLE gene. The above genes can be considered as the candidate genes for yak with higher fat amount in molecular breeding in the future. This study can provide a theoretical basis for improving the meat quality and breeding of yaks.

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.

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