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Increased serum cholesterol and long-chain fatty acid levels are associated with the efficacy of nivolumab in patients with non-small cell lung cancer.
Karayama, M, Inui, N, Inoue, Y, Yoshimura, K, Mori, K, Hozumi, H, Suzuki, Y, Furuhashi, K, Fujisawa, T, Enomoto, N, et al
Cancer immunology, immunotherapy : CII. 2022;(1):203-217
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Abstract
BACKGROUND Lipids have immunomodulatory functions and the potential to affect cancer immunity. METHODS The associations of pretreatment serum cholesterol and long-chain fatty acids with the objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were evaluated in 148 patients with non-small cell lung cancer who received nivolumab. RESULTS When each lipid was separately evaluated, increased low-density lipoprotein (LDL)-cholesterol (P < 0.001), high-density lipoprotein (HDL)-cholesterol (P = 0.014), total cholesterol (P = 0.007), lauric acid (P = 0.015), myristic acid (P = 0.022), myristoleic acid (P = 0.035), stearic acid (P = 0.028), linoleic acid (P = 0.005), arachidic acid (P = 0.027), eicosadienoic acid (P = 0.017), dihomo-γ-linolenic acid (P = 0.036), and behenic acid levels (P = 0.032) were associated with longer PFS independent of programmed death ligand 1 (PD-L1) expression. Meanwhile, increased LDL-cholesterol (P < 0.001), HDL-cholesterol (P = 0.009), total cholesterol (P = 0.036), linoleic acid (P = 0.014), and lignoceric acid levels (P = 0.028) were associated with longer OS independent of PD-L1 expression. When multiple lipids were evaluated simultaneously, LDL-cholesterol (P = 0.003), HDL-cholesterol (P = 0.036), and lauric acid (P = 0.036) were independently predictive of PFS, and LDL-cholesterol (P = 0.008) and HDL-cholesterol (P = 0.031) were predictive of OS. ORR was not associated with any serum lipid. CONCLUSIONS Based on the association of prolonged survival in patients with increased serum cholesterol and long-chain fatty acid levels, serum lipid levels may be useful for predicting the efficacy of immune checkpoint inhibitor therapy.
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Dietary Fatty Acids at the Crossroad between Obesity and Colorectal Cancer: Fine Regulators of Adipose Tissue Homeostasis and Immune Response.
Del Cornò, M, Varì, R, Scazzocchio, B, Varano, B, Masella, R, Conti, L
Cells. 2021;(7)
Abstract
Colorectal cancer (CRC) is among the major threatening diseases worldwide, being the third most common cancer, and a leading cause of death, with a global incidence expected to increase in the coming years. Enhanced adiposity, particularly visceral fat, is a major risk factor for the development of several tumours, including CRC, and represents an important indicator of incidence, survival, prognosis, recurrence rates, and response to therapy. The obesity-associated low-grade chronic inflammation is thought to be a key determinant in CRC development, with the adipocytes and the adipose tissue (AT) playing a significant role in the integration of diet-related endocrine, metabolic, and inflammatory signals. Furthermore, AT infiltrating immune cells contribute to local and systemic inflammation by affecting immune and cancer cell functions through the release of soluble mediators. Among the factors introduced with diet and enriched in AT, fatty acids (FA) represent major players in inflammation and are able to deeply regulate AT homeostasis and immune cell function through gene expression regulation and by modulating the activity of several transcription factors (TF). This review summarizes human studies on the effects of dietary FA on AT homeostasis and immune cell functions, highlighting the molecular pathways and TF involved. The relevance of FA balance in linking diet, AT inflammation, and CRC is also discussed. Original and review articles were searched in PubMed without temporal limitation up to March 2021, by using fatty acid as a keyword in combination with diet, obesity, colorectal cancer, inflammation, adipose tissue, immune cells, and transcription factors.
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Lipids in the tumor microenvironment: From cancer progression to treatment.
Corn, KC, Windham, MA, Rafat, M
Progress in lipid research. 2020;:101055
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Abstract
Over the past decade, the study of metabolic abnormalities in cancer cells has risen dramatically. Cancer cells can thrive in challenging environments, be it the hypoxic and nutrient-deplete tumor microenvironment or a distant tissue following metastasis. The ways in which cancer cells utilize lipids are often influenced by the complex interactions within the tumor microenvironment and adjacent stroma. Adipocytes can be activated by cancer cells to lipolyze their triglyceride stores, delivering secreted fatty acids to cancer cells for uptake through numerous fatty acid transporters. Cancer-associated fibroblasts are also implicated in lipid secretion for cancer cell catabolism and lipid signaling leading to activation of mitogenic and migratory pathways. As these cancer-stromal interactions are exacerbated during tumor progression, fatty acids secreted into the microenvironment can impact infiltrating immune cell function and phenotype. Lipid metabolic abnormalities such as increased fatty acid oxidation and de novo lipid synthesis can provide survival advantages for the tumor to resist chemotherapeutic and radiation treatments and alleviate cellular stresses involved in the metastatic cascade. In this review, we highlight recent literature that demonstrates how lipids can shape each part of the cancer lifecycle and show that there is significant potential for therapeutic intervention surrounding lipid metabolic and signaling pathways.
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Urinary fatty acid and retinol binding protein-4 predict CKD progression in severe NAFLD patients with hypertension: 4-year study with clinical and experimental approaches.
Tsai, YL, Liu, CW, Huang, SF, Yang, YY, Lin, MW, Huang, CC, Li, TH, Huang, YH, Hou, MC, Lin, HC
Medicine. 2020;(2):e18626
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Abstract
Detection of the chronic kidney disease (CKD) progression can begin early intervention to improve the prognosis of severe non-alcoholic fatty liver disease (NAFLD). This bi-directional cross-sectional study evaluates the roles of fatty acid-binding protein (FABP) and retinol binding protein (RBP4), which are produced from inflamed liver, adipose tissue and immune cells, for the prediction of CKD progression in severe NAFLD. Ninety severe NAFLD patients with hypertension and proteinuria (NAFLDHTN) were enrolled and divided into CKD (n = 39) and non-CKD groups (n = 51). Among 39 NAFLDHTN patients, 18 cases were categorized as CKD progression group. In comparison with CKD stable group (n = 21), the positive correlation between fold change values of hepatic fibrotic score (KPa), urinary FABP4 or urinary RBP4 versus severity of albuminuria were noted among CKD progression group. On multivariate analysis, high body mass index (BMI, >25 kg/m), high hepatic fibrosis score (>9.5 KPa), high urinary level of vascular cell adhesion molecule-1 (VCAM-1, >2239 μg/g cr), high urinary level of FABP4 (>115 ng/g cr) and high urinary level of RBP4 (>33.5 mg/g cr) are 5 independent predictors for progressive CKD during 24 months of follow-up. Synergetic effect was noted among these 5 risk factors for the prediction of CKD progression in NAFLDHTN patients. The in vitro experiments revealed that both FABP4 and RBP4 directly enhanced albumin-induced ER stress and apoptosis of human renal tubular epithelial cell line HK-2 cells and human podocytes cell lines. Through clinical and experimental approaches, this study revealed new 5 synergetic predictors including high BMI, hepatic fibrosis score, urinary level of VCAM-1, urinary level of FABP4 and RBP4, for the CKD progression in severe NAFLD patients with hypertension and proteinuria.
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Saturated fatty acids, obesity, and the nucleotide oligomerization domain-like receptor protein 3 (NLRP3) inflammasome in asthmatic patients.
Wood, LG, Li, Q, Scott, HA, Rutting, S, Berthon, BS, Gibson, PG, Hansbro, PM, Williams, E, Horvat, J, Simpson, JL, et al
The Journal of allergy and clinical immunology. 2019;(1):305-315
Abstract
BACKGROUND Both obesity and high dietary fat intake activate the nucleotide oligomerization domain-like receptor protein 3 (NLRP3) inflammasome. OBJECTIVE We aimed to examine NLRP3 inflammasome activity in the airways of obese asthmatic patients after macronutrient overload and in immune cells challenged by inflammasome triggers. METHODS Study 1 was a cross-sectional observational study of nonobese (n = 51) and obese (n = 76) asthmatic adults. Study 2 was a randomized, crossover, acute feeding study in 23 asthmatic adults (n = 12 nonobese and n = 11 obese subjects). Subjects consumed 3 isocaloric meals on 3 separate occasions (ie, saturated fatty acid, n-6 polyunsaturated fatty acid, and carbohydrate) and were assessed at 0 and 4 hours. For Studies 1 and 2, airway inflammation was measured based on sputum differential cell counts, IL-1β protein levels (ELISA), and sputum cell gene expression (Nanostring nCounter). In Study 3 peripheral blood neutrophils and monocytes were isolated by using Ficoll density gradient and magnetic bead separation and incubated with or without palmitic acid, LPS, or TNF-α for 24 hours, and IL-1β release was measured (ELISA). RESULTS In Study 1 NLRP3 and nucleotide oligomerization domain 1 (NOD1) gene expression was upregulated, and sputum IL-1β protein levels were greater in obese versus nonobese asthmatic patients. In Study 2 the saturated fatty acid meal led to increases in sputum neutrophil percentages and sputum cell gene expression of Toll-like receptor 4 (TLR4) and NLRP3 at 4 hours in nonobese asthmatic patients. In Study 3 neutrophils and monocytes released IL-1β when challenged with a combination of palmitic acid and LPS or TNF-α. CONCLUSION The NLRP3 inflammasome is a potential therapeutic target in asthmatic patients. Behavioral interventions that reduce fatty acid exposure, such as weight loss and dietary saturated fat restriction, warrant further exploration.
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Serum very long-chain fatty acid-containing lipids predict response to immune checkpoint inhibitors in urological cancers.
Mock, A, Zschäbitz, S, Kirsten, R, Scheffler, M, Wolf, B, Herold-Mende, C, Kramer, R, Busch, E, Jenzer, M, Jäger, D, et al
Cancer immunology, immunotherapy : CII. 2019;(12):2005-2014
Abstract
Checkpoint inhibitors (CPI) have significantly changed the therapeutic landscape of oncology. We adopted a non-invasive metabolomic approach to understand immunotherapy response and failure in 28 urological cancer patients. In total, 134 metabolites were quantified in patient sera before the first, second, and third CPI doses. Modeling the association between metabolites and CPI response and patient characteristics revealed that one predictive metabolite class (n = 9/10) were very long-chain fatty acid-containing lipids (VLCFA-containing lipids). The best predictive performance was achieved through a multivariate model, including age and a centroid of VLCFA-containing lipids prior to first immunotherapy (sensitivity: 0.850, specificity: 0.825, ROC: 0.935). We hypothesize that the association of VLCFA-containing lipids with CPI response is based on enhanced peroxisome signaling in T cells, which results in a switch to fatty acid catabolism. Beyond use as a novel predictive non-invasive biomarker, we envision that nutritional supplementation with VLCFA-containing lipids might serve as an immuno sensitizer.
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Short-chain fatty acids: a link between prebiotics and microbiota in chronic kidney disease.
Esgalhado, M, Kemp, JA, Damasceno, NR, Fouque, D, Mafra, D
Future microbiology. 2017;:1413-1425
Abstract
Under physiologic conditions, the human gut microbiota performs several activities essential to the body health. In contrast, their imbalances exacerbate some actions which can promote a cascade of metabolic abnormalities, and vice versa. Numerous diseases, including chronic kidney disease, are associated with gut microbiota imbalance, and among several strategies to re-establish gut symbiosis, prebiotics seem to represent an effective nonpharmacological approach. Prebiotics fermentation by gut microbiota produce short-chain fatty acids, which improve the gut barrier integrity and function, and modulate the glucose and lipid metabolism as well as the inflammatory response and immune system. Therefore, this literature review intends to discuss the beneficial effects of prebiotics in human health through short-chain fatty acids production, with a particular interest on chronic kidney disease.
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The effects of exogenous fatty acids and niacin on human monocyte-macrophage plasticity.
Montserrat-de la Paz, S, Rodriguez, D, Cardelo, MP, Naranjo, MC, Bermudez, B, Abia, R, Muriana, FJG, Lopez, S
Molecular nutrition & food research. 2017;(8)
Abstract
SCOPE Macrophage plasticity allows adapting to different environments, having a dual activity in inflammatory-related diseases. Our hypothesis is that the type of dietary fatty acids into human postprandial triglyceride-rich lipoproteins (TRLs), alone or in combination with niacin (vitamin B3), could modulate the plasticity of monocytes-macrophages. METHODS AND RESULTS We isolated TRLs at the postprandial peak from blood samples of healthy volunteers after the ingestion of a meal rich in saturated fatty acids (SFAs), monounsaturated fatty acids (MUFAs) or MUFAs plus omega-3 long-chain polyunsaturated fatty acids (LCPUFAs). Autologous monocytes isolated at fasting were first induced to differentiate into naïve macrophages. We observed that postprandial TRL-MUFAs, particularly in combination with niacin, enhance competence to monocytes to differentiate and polarise into M2 macrophages. Postprandial TRL-SFAs made polarised macrophages prone to an M1 phenotype. In contrast to dietary SFAs, dietary MUFAs in the meals plus immediate-release niacin primed circulating monocytes for a reduced postprandial pro-inflammatory profile. CONCLUSION Our study underlines a role of postprandial TRLs as a metabolic entity in regulating the plasticity of the monocyte-macrophage lineage and also brings an understanding of the mechanisms by which dietary fatty acids are environmental factors fostering the innate immune responsiveness in humans.
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Function and Dysfunction of Adipose Tissue.
Matafome, P, Seiça, R
Advances in neurobiology. 2017;:3-31
Abstract
Adipose tissue is an endocrine organ which is responsible for postprandial uptake of glucose and fatty acids, consequently producing a broad range of adipokines controlling several physiological functions like appetite, insulin sensitivity and secretion, immunity, coagulation, and vascular tone, among others. Many aspects of adipose tissue pathophysiology in metabolic diseases have been described in the last years. Recent data suggest two main factors for adipose tissue dysfunction: accumulation of nonesterified fatty acids and their secondary products and hypoxia. Both of these factors are thought to be on the basis of low-grade inflammatory activation, further increasing metabolic dysregulation in adipose tissue. In turn, inflammation is involved in the inhibition of substrate uptake, alteration of the secretory profile, stimulation of angiogenesis, and recruitment of further inflammatory cells, which creates an inflammatory feedback in the tissue and is responsible for long-term establishment of insulin resistance.
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Greasy tactics in the plant-pathogen molecular arms race.
Boyle, PC, Martin, GB
Journal of experimental botany. 2015;(6):1607-16
Abstract
The modification of proteins by the attachment of fatty acids is a targeting tactic involved in mechanisms of both plant immunity and bacterial pathogenesis. The plant plasma membrane (PM) is a key battleground in the war against disease-causing microbes. This membrane is armed with an array of sensor proteins that function as a surveillance system to detect invading pathogens. Several of these sensor proteins are directed to the plasma membrane through the covalent addition of fatty acids, a process termed fatty acylation. Phytopathogens secrete effector proteins into the plant cell to subvert these surveillance mechanisms, rendering the host susceptible to infection. The targeting of effectors to specific locales within plant cells, particularly the internal face of the host PM, is critical for their virulence function. Several bacterial effectors hijack the host fatty acylation machinery to be modified and directed to this contested locale. To find and fight these fatty acylated effectors the plant leverages lipid-modified intracellular sensors. This review provides examples featuring how fatty acylation is a battle tactic used by both combatants in the molecular arms race between plants and pathogens. Also highlighted is the exploitation of a specific form of host-mediated fatty acid modification, which appears to be exclusively employed by phytopathogenic effector proteins.