scholarly journals Cathepsin Inhibition Modulates Metabolism and Polarization of Tumor-Associated Macrophages

Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2579
Author(s):  
Diana Oelschlaegel ◽  
Tommy Weiss Sadan ◽  
Seth Salpeter ◽  
Sebastian Krug ◽  
Galia Blum ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Metabolism ◽  
Immune Cells ◽  
Fatty Acid Synthase ◽  
Acid Metabolism ◽  
Metabolic Reprogramming ◽  
Marker Genes ◽  
Tumor Associated Macrophages ◽  
Cathepsin Activity ◽  
The Impact

Stroma-infiltrating immune cells, such as tumor-associated macrophages (TAM), play an important role in regulating tumor progression and chemoresistance. These effects are mostly conveyed by secreted mediators, among them several cathepsin proteases. In addition, increasing evidence suggests that stroma-infiltrating immune cells are able to induce profound metabolic changes within the tumor microenvironment. In this study, we aimed to characterize the impact of cathepsins in maintaining the TAM phenotype in more detail. For this purpose, we investigated the molecular effects of pharmacological cathepsin inhibition on the viability and polarization of human primary macrophages as well as its metabolic consequences. Pharmacological inhibition of cathepsins B, L, and S using a novel inhibitor, GB111-NH2, led to changes in cellular recycling processes characterized by an increased expression of autophagy- and lysosome-associated marker genes and reduced adenosine triphosphate (ATP) content. Decreased cathepsin activity in primary macrophages further led to distinct changes in fatty acid metabolites associated with increased expression of key modulators of fatty acid metabolism, such as fatty acid synthase (FASN) and acid ceramidase (ASAH1). The altered fatty acid profile was associated with an increased synthesis of the pro-inflammatory prostaglandin PGE2, which correlated with the upregulation of numerous NFkB-dependent pro-inflammatory mediators, including interleukin-1 (IL-1), interleukin-6 (IL-6), C-C motif chemokine ligand 2 (CCL2), and tumor necrosis factor-alpha (TNFα). Our data indicate a novel link between cathepsin activity and metabolic reprogramming in macrophages, demonstrated by a profound impact on autophagy and fatty acid metabolism, which facilitates a pro-inflammatory micromilieu generally associated with enhanced tumor elimination. These results provide a strong rationale for therapeutic cathepsin inhibition to overcome the tumor-promoting effects of the immune-evasive tumor micromilieu.

FC 102PD INDUCED ARTERIOLAR AND PERITONEAL PATHOMECHANISMS ARE PARTIALLY REVERSED AFTER KIDNEY TRANSPLANTATION

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Conghui Zhang ◽  
Maria Bartosova ◽  
Betti Schaefer ◽  
Rebecca Herzog ◽  
Rimante Cerkauskiene ◽  
...  
Keyword(s):  
Kidney Transplantation ◽  
Fatty Acid ◽  
Fatty Acid Metabolism ◽  
Fatty Acid Synthase ◽  
Molecular Mechanisms ◽  
Acid Metabolism ◽  
Parietal Peritoneum ◽  
Gene Set Enrichment Analysis ◽  
Biological Processes ◽  
Cell Counts

Abstract Background and Aims Due to the unphysiological composition of PD fluids, chronic peritoneal dialysis (PD) induces progressive peritoneal fibrosis, hypervascularization, and vasculopathy. The evolution of the PD membrane and vasculopathy following kidney transplantation (KTx) is largely unknown. Method Arteriolar and peritoneal tissues were obtained from 107 children with chronic kidney disease (CKD5), 72 children on PD (treated with neutral pH PD fluids, with low glucose degradation product content, GDP) and 21 children, who underwent KTx 4-5 weeks after a median 21 months of PD. Specimen underwent standardized digital quantitative histomorphometry. Molecular mechanisms were studied in omental arterioles microdissected from surrounding fat by multi-omics followed by Gene Set Enrichment Analysis (GSEA); key findings were validated in parietal tissues of independent, matched cohorts by quantitative immunohistochemistry (n=15/group). Results Arteriolar transcriptome and proteome GSEA revealed suppression of leucocyte migration and T-cell activation / secretory pathways regulation, of sprouting angiogenesis biological processes and of epithelial proliferation and cell cycle after KTx as compared to PD. Lipid / fatty acid metabolism, autophagy and ATP synthesis pathways were activated. Transcriptome analysis including KTx, PD and CKD5 specifically attributed regulation of arteriolar lipid and fatty acid metabolism to transplantation and comprised 140 transcripts; their regulation was confirmed on the proteome level. Hub gene fatty acid synthase was identified by protein interaction analysis (string-db.org). 15 arteriolar genes activated by PD were inactivated after KTx and included glucose metabolisms and cytoskeleton related transcripts. 24 transcripts and 10 corresponding proteins induced by PD were still active after KTx and associated with biological processes related to TGF-ß signaling, fibrosis and mineral absorption. In line with arteriolar multi-omics findings, peritoneal hypervascularization induced by chronic PD was reversed after Tx to CKD5 level. CD45 positive tissue infiltrating leucocytes count was reduced by 40% and was independently associated with microvessel density in multivariable analysis including PD vintage, daily GDP exposure and recent KTx. Peritoneal lymphatic vessel density, submesothelial thickness, activated fibroblast, fibrin deposit, macrophage and EMT cell counts remained unchanged after KTx compared to PD. Arteriolar lumen to vessel ratios (a marker of vasculopathy) were similar in both groups. Vessel-homeostasis-related proteins in independent, matched cohorts demonstrated increased caspase-3 abundance in peritoneal arterioles after KTx. Arteriolar VEGF-A, thrombospondin, angiopoietin1/2, and hypoxia-inducible factor-1 (HIF-1a) were unchanged, while submesothelial HIF-1a and angiopoietin1/2 were decreased after Tx, favoring vessel maturation. The abundance of the key driver of fibrosis, TGF-ß-effector pSMAD2/3, was unchanged in the peritoneum and arterioles after Tx. Conclusion Our multi-omics analyses of fat covered omental arterioles, not directly exposed to PD fluids, demonstrate inhibition of PD induced immune response and angiogenesis pathways, of glucose metabolism and cytoskeleton regulation to levels similar as seen in children with CKD5. Arteriolar lipid and fatty acid metabolism is selectively altered after KTx. Reversal of low GDP PD induced hypervascularization and inflammation of the parietal peritoneum after KTx, mirror molecular changes in omental arterioles, while profibrotic activity persists after KTx in omental arterioles and in the parietal peritoneum.

scholarly journals Fatty acid synthase promotes breast cancer metastasis by mediating changes in fatty acid metabolism

2020 ◽  
Vol 21 (1) ◽  
pp. 1-1
Author(s):  
Shuo Xu ◽  
Tingting Chen ◽  
Lihua Dong ◽  
Tao Li ◽  
Hui Xue ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Fatty Acid ◽  
Fatty Acid Metabolism ◽  
Fatty Acid Synthase ◽  
Cancer Metastasis ◽  
Acid Metabolism ◽  
Breast Cancer Metastasis

scholarly journals The effect of fetal pig size and stage of gestation on tissue fatty acid metabolism and profile

Reproduction ◽  
2005 ◽  
Vol 129 (6) ◽  
pp. 757-763 ◽  
Author(s):  
Christopher J McNeil ◽  
Angela M Finch ◽  
Kenneth R Page ◽  
Steve D Clarke ◽  
Cheryl J Ashworth ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fetal Growth ◽  
Fatty Acid Metabolism ◽  
Fatty Acid Synthase ◽  
Porcine Model ◽  
Acid Metabolism ◽  
Fatty Acid Status ◽  
Δ5 Desaturase ◽  
Acid Status ◽  
Δ6 Desaturase

The fetus requires an adequate supply of fatty acids for optimum growth and development. It has been hypothesized that reduced activity of enzymes of fatty acid metabolism could contribute to inadequate fetal growth. In a porcine model of differential fetal growth we examined heart and liver fatty acid synthase, Δ5-desaturase and Δ6-desaturase gene expression and measured hepatic fatty acid profile to assess long-chain polyunsaturated fatty acid status. On gestation days 45, 65 and 100 sows were killed and tissues extracted from an average-sized fetus and the smallest fetus from each litter. As early as day 45, considerable hepatic Δ5- and Δ6-desaturase was detected, and this expression significantly increased as gestation progressed. In contrast, cardiac desaturase expression remained stable with time. Fatty acid synthase expression was greatest at day 65 in the liver, but was not expressed in the heart. Overall, the smallest fetus did not exhibit reduced tissue Δ5- or Δ6-desaturase expression or compromised polyunsaturated fatty acid status at any stage. In fact, small fetuses expressed more cardiac Δ5-desaturase than their average-sized siblings, possibly in response to a stress to the heart. It is clear from this study that fatty acid metabolism changes markedly as gestation progresses, and reduced fatty acid supply does not cause inadequate growth in this porcine model of fetal development.

RIPK3 Orchestrates Fatty Acid Metabolism in Tumor-Associated Macrophages and Hepatocarcinogenesis

2020 ◽  
Vol 8 (5) ◽  
pp. 710-721 ◽  
Author(s):  
Lei Wu ◽  
Xiao Zhang ◽  
Lu Zheng ◽  
Huakan Zhao ◽  
Guifang Yan ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Metabolism ◽  
Acid Metabolism ◽  
Tumor Associated Macrophages

scholarly journals Lipid droplet‐dependent fatty acid metabolism controls the immune suppressive phenotype of tumor‐associated macrophages

2019 ◽  
Vol 11 (11) ◽  
Author(s):  
Hao Wu ◽  
Yijie Han ◽  
Yasmina Rodriguez Sillke ◽  
Hongzhang Deng ◽  
Sophiya Siddiqui ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Lipid Droplet ◽  
Fatty Acid Metabolism ◽  
Acid Metabolism ◽  
Tumor Associated Macrophages ◽  
Suppressive Phenotype

scholarly journals Multi-Omics Analysis of Fatty Acid Metabolism in Thyroid Carcinoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Jinghui Lu ◽  
Yankun Zhang ◽  
Min Sun ◽  
Changyuan Ding ◽  
Lei Zhang ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Fatty Acid ◽  
Lipid Metabolism ◽  
Thyroid Carcinoma ◽  
Fatty Acid Metabolism ◽  
Acid Metabolism ◽  
Metabolic Reprogramming ◽  
Clinical Samples ◽  
Integrated Analysis ◽  
Additional Energy

ObjectivePapillary thyroid carcinoma (PTC) accounts for the majority of thyroid cancer and affects a large number of individuals. The pathogenesis of PTC has not been completely elucidated thus far. Metabolic reprogramming is a common feature in tumours. Our previous research revealed the reprogramming of lipid metabolism in PTC. Further studies on lipid metabolism reprogramming may help elucidate the pathogenesis of PTC.MethodsClinical samples of PTC and para-tumour tissue were analysed using lipidomic, proteomic, and metabolomic approaches. A multi-omics integrative strategy was adopted to identify the important pathways in PTC. The findings were further confirmed using western blotting, tissue microarray, bioinformatics, and cell migration assays.ResultsMulti-omics data and the results of integrated analysis revealed that the three steps of fatty acid metabolism (hydrolysis, transportation, and oxidation) were significantly enhanced in PTC. Especially, the expression levels of LPL, FATP2, and CPT1A, three key enzymes in the respective steps, were elevated in PTC. Moreover, LPL, FATP2 and CPT1A expression was associated with the TNM stage, lymph node metastasis of PTC. Moreover, high levels of FATP2 and CPT1A contributed to poor prognosis of PTC. In addition, ectopic overexpression of LPL, FATP2 and CPT1A can each promote the migration of thyroid cancer cells.ConclusionsOur data suggested that enhanced fatty acid metabolism supplied additional energy and substrates for PTC progression. This may help elucidating the underlying mechanism of PTC pathogenesis and identifying the potential therapeutic targets for PTC.

scholarly journals The impact of FADS genetic variants on ω6 polyunsaturated fatty acid metabolism in African Americans

BMC Genetics ◽  
2011 ◽  
Vol 12 (1) ◽  
pp. 50 ◽  
Author(s):  
Rasika A Mathias ◽  
Susan Sergeant ◽  
Ingo Ruczinski ◽  
Dara G Torgerson ◽  
Christina E Hugenschmidt ◽  
...  
Keyword(s):  
Fatty Acid ◽  
African Americans ◽  
Polyunsaturated Fatty Acid ◽  
Fatty Acid Metabolism ◽  
Genetic Variants ◽  
Acid Metabolism ◽  
The Impact

scholarly journals Influence of Disorders of Fatty Acid Metabolism, Arterial Wall Hypoxia, and Intraplaque Hemorrhages on Lipid Accumulation in Atherosclerotic Vessels

2021 ◽  
Vol 6 (2) ◽  
pp. 70-80
Author(s):  
A. N. Osipenko
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Metabolism ◽  
Arterial Wall ◽  
Acid Metabolism ◽  
Vascular Wall ◽  
Vasa Vasorum ◽  
Erythrocyte Membranes ◽  
Cholesterol Accumulation ◽  
Arterial Intima ◽  
The Impact

The review describes a number of competing views on the main causes of cholesterol accumulation in atherosclerotic vessels. On the one hand, unregulated cholesterol influx into arterial intima is primarily related to the increasing proportion of atherogenic lipoproteins in the lipoprotein spectrum of blood. On the other hand, the leading role in this process is assigned to the increased permeability of endothelium for atherogenic lipoproteins. The increased ability of arterial intima connective tissue to bind atherogenic blood lipoproteins is also considered to be the leading cause of cholesterol accumulation in the vascular wall. The key role in cholesterol accumulation is also assigned to unregulated (by a negative feedback mechanism) absorption of atherogenic lipoproteins by foam cells. It is suggested that the main cause of abundant cholesterol accumulation in atherosclerotic vessels is significant inflow of this lipid into the vascular wall during vasa vasorum hemorrhages.The article also provides arguments, according to which disorder of fatty acid metabolism in arterial wall cells can initiate accumulation of neutral lipids in them, contribute to the inflammation and negatively affect the mechanical conditions around the vasa vasorum in the arterial walls. As a result, the impact of pulse waves on the luminal surface of the arteries will lead to frequent hemorrhages of these microvessels. At the same time, adaptive-muscular intima hyperplasia, which develops in arterial channel areas subjected to high hemodynamic loads, causes local hypoxia in a vascular wall. As a result, arterial wall cells undergo even more severe lipid transformation. Hypoxia also stimulates vascularization of the arterial wall, which contributes to hemorrhages in it. With hemorrhages, free erythrocyte cholesterol penetrates into the forming atherosclerotic plaque, a part of this cholesterol forms cholesterol esters inside the arterial cells. The saturation of erythrocyte membranes with this lipid in conditions of hypercholesterolemia and atherogenic dyslipoproteinemia contributes to the process of cholesterol accumulation in arteries. 

Abstract 404: Acute Knock-down of Cardiac Peroxisome Proliferator Activated Receptor α Does Not Impair Cardiac Function

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Natasha Fillmore ◽  
Junhui Sun ◽  
Danielle Springer ◽  
Elizabeth Murphy
Keyword(s):  
Heart Failure ◽  
Fatty Acid ◽  
Cardiac Function ◽  
Fatty Acid Metabolism ◽  
Acid Metabolism ◽  
Body Weight Gain ◽  
Baseline Heart Rate ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
The Impact

Alterations in glucose and fatty acid metabolism are believed to contribute to the development of heart failure. Peroxisome Proliferator Activated Receptor α (PPARα) is a transcription factor that regulates fatty acid metabolism and is frequently reported to be reduced in heart failure. However, it is controversial whether this decline in PPARα mediates the development of cardiac hypertrophy and heart failure. To improve our understanding of the role of cardiac PPARα we generated a tamoxifen inducible cardiac-specific PPARα knockout mouse (cPPAR -/- ). Control (Mer-Cre-Mer and Flox -/- ) mice and cPPAR -/- (Mer-Cre-Mer and Flox +/+ ) mice were treated with tamoxifen at ~2.5 months and were studied 5 weeks after treatment. We verified loss of cardiac PPARα using western blot. cPPAR -/- mice appear healthy with normal body weight gain and survival. To examine the impact of cardiac deletion of PPARα on cardiac function we performed echocardiography on control and cPPAR -/- . There was no reduction in systolic function between control and cPPAR -/- mice. Ejection fraction (Control, 56.3±0.9; cPPAR -/- , 59.7±0.1) and fractional shortening (Control, 29.1±0.5; cPPAR -/- , 31.5±0.1) were similar in cPPAR -/- compared to control hearts. Interestingly however, baseline heart rate was significantly lower in cPPAR -/- versus control mice (Control, 531.3±18.3; cPPAR -/- , 459.8±2.9 bpm). In addition to having normal cardiac function, heart weights were similar between control and cPPAR -/- mice. Overall, these data indicate that an acute reduction in myocardial PPARα per se does not cause cardiac dysfunction. However these data do not exclude the possibility that loss of PPARα could drive cardiac pathology in the context of other signals.

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