scholarly journals Multimodal Metabolic Imaging Reveals Pigment Reduction and Lipid Accumulation in Metastatic Melanoma

BME Frontiers ◽  
2021 ◽  
Vol 2021 ◽  
pp. 1-17
Author(s):  
Hyeon Jeong Lee ◽  
Zhicong Chen ◽  
Marianne Collard ◽  
Fukai Chen ◽  
Jiaji G. Chen ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Early Diagnosis ◽  
Metastatic Melanoma ◽  
Lipid Accumulation ◽  
Fatty Acid Uptake ◽  
Metabolic Reprogramming ◽  
Low Grade ◽  
Acid Uptake ◽  
Subcellular Level ◽  
Metabolic Signatures

Objective and Impact Statement. Molecular signatures are needed for early diagnosis and improved treatment of metastatic melanoma. By high-resolution multimodal chemical imaging of human melanoma samples, we identify a metabolic reprogramming from pigmentation to lipid droplet (LD) accumulation in metastatic melanoma. Introduction. Metabolic plasticity promotes cancer survival and metastasis, which promises to serve as a prognostic marker and/or therapeutic target. However, identifying metabolic alterations has been challenged by difficulties in mapping localized metabolites with high spatial resolution. Methods. We developed a multimodal stimulated Raman scattering and pump-probe imaging platform. By time-domain measurement and phasor analysis, our platform allows simultaneous mapping of lipids and pigments at a subcellular level. Furthermore, we identify the sources of these metabolic signatures by tracking deuterium metabolites at a subcellular level. By validation with mass spectrometry, a specific fatty acid desaturase pathway was identified. Results. We identified metabolic reprogramming from a pigment-containing phenotype in low-grade melanoma to an LD-rich phenotype in metastatic melanoma. The LDs contain high levels of cholesteryl ester and unsaturated fatty acids. Elevated fatty acid uptake, but not de novo lipogenesis, contributes to the LD-rich phenotype. Monounsaturated sapienate, mediated by FADS2, is identified as an essential fatty acid that promotes cancer migration. Blocking such metabolic signatures effectively suppresses the migration capacity both in vitro and in vivo. Conclusion. By multimodal spectroscopic imaging and lipidomic analysis, the current study reveals lipid accumulation, mediated by fatty acid uptake, as a metabolic signature that can be harnessed for early diagnosis and improved treatment of metastatic melanoma.

scholarly journals FADS2-mediated fatty acid desaturation and cholesterol esterification are signatures of metabolic reprogramming during melanoma progression

2020 ◽  
Author(s):  
Hyeon Jeong Lee ◽  
Zhicong Chen ◽  
Marianne Collard ◽  
Jiaji G Chen ◽  
Muzhou Wu ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Metastatic Melanoma ◽  
Therapeutic Potential ◽  
Fatty Acid Uptake ◽  
Melanoma Cells ◽  
Metabolic Reprogramming ◽  
Cholesterol Esterification ◽  
Low Grade ◽  
Acid Uptake ◽  
Melanoma Progression

AbstractIdentifying metabolic alterations in disease progression has been challenged by difficulties in tracking metabolites at sub-cellular level. Here, by high-resolution stimulated Raman scattering and pump-probe imaging and spectral phasor analysis of melanoma cells grouped by MITF/AXL expression pattern and of human patient tissues paired by primary and metastatic status, we identify a metabolic switch from a pigment-containing phenotype in low-grade melanoma to a lipid-rich phenotype in metastatic melanoma. The lipids found in MITFlow/AXLhigh melanoma cells contain high levels of cholesteryl ester (CE) and unsaturated fatty acid species. Elevated fatty acid uptake activity in MITFlow/AXLhigh melanoma contributes to the lipid-rich phenotype, and inhibiting fatty acid uptake suppresses cell migration. Importantly, monounsaturated sapienate is identified as an essential fatty acid that effectively promotes cancer migration. Blocking either FADS2-mediated lipid desaturation or SOAT-mediated cholesterol esterification effectively suppresses the migration capacity of melanoma in vitro and in vivo, indicating the therapeutic potential of targeting these metabolic pathways in metastatic melanoma. Collectively, our results reveal metabolic reprogramming during melanoma progression, and highlight metabolic signatures that could serve as targets for metastatic melanoma treatment and diagnosis.

scholarly journals Lipid Accumulation and Chronic Kidney Disease

Nutrients ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 722 ◽  
Author(s):  
Zhibo Gai ◽  
Tianqi Wang ◽  
Michele Visentin ◽  
Gerd Kullak-Ublick ◽  
Xianjun Fu ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Fatty Acids ◽  
Fatty Acid ◽  
Kidney Disease ◽  
Lipid Accumulation ◽  
Scavenger Receptor ◽  
Fatty Acid Uptake ◽  
Lipid Lowering ◽  
Fatty Acid Transport ◽  
Acid Uptake

Obesity and hyperlipidemia are the most prevalent independent risk factors of chronic kidney disease (CKD), suggesting that lipid accumulation in the renal parenchyma is detrimental to renal function. Non-esterified fatty acids (also known as free fatty acids, FFA) are especially harmful to the kidneys. A concerted, increased FFA uptake due to high fat diets, overexpression of fatty acid uptake systems such as the CD36 scavenger receptor and the fatty acid transport proteins, and a reduced β-oxidation rate underlie the intracellular lipid accumulation in non-adipose tissues. FFAs in excess can damage podocytes, proximal tubular epithelial cells and the tubulointerstitial tissue through various mechanisms, in particular by boosting the production of reactive oxygen species (ROS) and lipid peroxidation, promoting mitochondrial damage and tissue inflammation, which result in glomerular and tubular lesions. Not all lipids are bad for the kidneys: polyunsaturated fatty acids (PUFA) such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) seem to help lag the progression of chronic kidney disease (CKD). Lifestyle interventions, especially dietary adjustments, and lipid-lowering drugs can contribute to improve the clinical outcome of patients with CKD.

scholarly journals Metabolic Reprogramming from Glycolysis to Fatty Acid Uptake and beta-Oxidation in Platinum-Resistant Cancer Cells

2021 ◽  
Author(s):  
Junjie Li ◽  
Yuying Tan ◽  
Guangyuan Zhao ◽  
Kai-Chih Huang ◽  
Horacio Cardenas ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Fatty Acid ◽  
Single Cell ◽  
Cancer Cell ◽  
Aerobic Glycolysis ◽  
Fatty Acid Uptake ◽  
Metabolic Reprogramming ◽  
De Novo Lipogenesis ◽  
Acid Uptake ◽  
Beta Oxidation

Increased aerobic glycolysis is widely considered as a hallmark of cancer. Yet, cancer cell metabolic reprograming during development of therapeutic resistance is under-studied. Here, through high-throughput stimulated Raman scattering imaging and single cell analysis, we found that cisplatin-resistant cells exhibit increased uptake of exogenous fatty acids, accompanied with decreased glucose uptake and de novo lipogenesis, indicating a reprogramming from glucose and glycolysis dependent to fatty acid uptake and beta-oxidation dependent anabolic and energy metabolism. A metabolic index incorporating measurements of glucose derived anabolism and fatty acid uptake correlates linearly to the level of resistance to cisplatin in ovarian cancer cell lines and in primary cells isolated from ovarian cancer patients. Mechanistically, the increased fatty acid uptake facilitates cancer cell survival under cisplatin-induced oxidative stress by enhancing energy production through beta-oxidation. Consequently, blocking fatty acid beta-oxidation by a small molecule inhibitor in combination with cisplatin or carboplatin synergistically suppressed ovarian cancer proliferation in vitro and growth of patient-derived xenograft in vivo. Collectively, these findings support a new way for rapid detection of cisplatin-resistance at single cell level and a new strategy for treatment of cisplatin-resistant tumors.

scholarly journals Role of caffeic and chlorogenic acid in the modulation of cellular fatty acid uptake

2020 ◽  
Vol 79 (OCE2) ◽  
Author(s):  
Mirko Marino ◽  
Massimiliano Tucci ◽  
Valentina Taverniti ◽  
Patrizia Riso ◽  
Marisa Porrini ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Chlorogenic Acid ◽  
Phenolic Acids ◽  
Lipid Accumulation ◽  
Biological Activities ◽  
Fatty Acid Uptake ◽  
Cellular Fatty Acid ◽  
Bioactive Molecules ◽  
Acid Uptake

AbstractPolyphenols are bioactive molecules widely distributed in numerous foods such as fruits, vegetables, tea, coffee, cocoa and beverages. Their main classification include flavonoids (i.e. flavonols, flavones, flavanones, flavanols, anthocyanins, and isoflavones), non-flavonoids (i.e. lignans and stilbens) and phenolic acids (i.e. hydroxycinnamic and hydroxybenzoic acids)(1). Caffeic acid (CA) and chlorogenic acid (CGA; an ester of CA and quinic acid) are the major representatives of hydroxycinnamic acids. Accumulating evidence has demonstrated that CA and CGA may exert different biological activities, including antioxidant, anti-inflammatory, antidiabetic, and antihypertensive(2). Despite these promising and diverse anti-atherosclerotic actions, investigations addressing the effect of CA and CGA on atherogenesis are scarce.The present study evaluated the capacity of CA and CGA to reduce lipid accumulation in macrophages derived from monocytic THP-1 cells. THP-1-derived macrophages were incubated with fatty acids (500 μM oleic/palmitic acid, 2:1 ratio) and different concentrations (from 0.03 to 3 μM) of CA and CGA, alone or in combination. Lipid accumulation was quantified spectrophotometrically (excitation: 544 nm, emission: 590 nm) with the fluorescent dye, Nile red. The fold increase compared to the control (without fatty acids) was calculated. In addition, the expression of several transcription factors including peroxisome proliferator-activated receptor gamma (PPARγ) and CCAAT/enhancer-binding protein (CEBP), as potential mechanisms involved in the regulation of lipid accumulation, was evaluated by real time PCR.Analysis of variance (ANOVA) was used to assess the effect of the different concentrations of CA and CGA on lipid accumulation in THP-1 macrophages following stimulation with FA.The preliminary results obtained have shown a significant increase in lipid accumulation following fatty acid exposure (p < 0.0001). Incubation with CA and CGA did not reduce lipid accumulation in THP-1 derived macrophages, while the combination of CA + CGA at 0.03, 0.3 and 3 μM (p < 0.01) decreased cellular fatty acid uptake at all concentrations tested by -28%, -32%, -23%, respectively. An apparent modulation of the transcriptional activity of PPARγ, but not CEBP, was observed following the combination of phenolic acids.In conclusion, the incubation of CA + CGA at physiologically relevant concentrations, but not the single compounds, seem to reduce the uptake of fatty acids in THP-1-derived macrophages. Further experiments are ongoing in order to confirm the findings obtained and to better identify the mechanisms of action involved in the reduction of lipid accumulation as a key phenomenon of atherogenesis.

scholarly journals Toward Quantitative in vivo Label-Free Tracking of Lipid Distribution in a Zebrafish Cancer Model

2021 ◽  
Vol 9 ◽  
Author(s):  
Marco Andreana ◽  
Caterina Sturtzel ◽  
Clemens P. Spielvogel ◽  
Laszlo Papp ◽  
Rainer Leitgeb ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Lipid Metabolism ◽  
Cancer Cells ◽  
Lipid Accumulation ◽  
Fatty Acid Uptake ◽  
Alternative Mechanism ◽  
Acid Uptake ◽  
Label Free ◽  
Tumor Onset

Cancer cells often adapt their lipid metabolism to accommodate the increased fatty acid demand for membrane biogenesis and energy production. Upregulation of fatty acid uptake from the environment of cancer cells has also been reported as an alternative mechanism. To investigate the role of lipids in tumor onset and progression and to identify potential diagnostic biomarkers, lipids are ideally imaged directly within the intact tumor tissue in a label-free way. In this study, we investigated lipid accumulation and distribution in living zebrafish larvae developing a tumor by means of coherent anti-Stokes Raman scattering microscopy. Quantitative textural features based on radiomics revealed higher lipid accumulation in oncogene-expressing larvae compared to healthy ones. This high lipid accumulation could reflect an altered lipid metabolism in the hyperproliferating oncogene-expressing cells.

scholarly journals Anterior gradient 2 increases long-chain fatty acid uptake via stabilizing FABP1 and facilitates lipid accumulation

2021 ◽  
Vol 17 (3) ◽  
pp. 834-847
Author(s):  
Yunqiu Wang ◽  
Mengqi Jia ◽  
Chuanjie Liang ◽  
Nan Sheng ◽  
Xiaodan Wang ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Lipid Accumulation ◽  
Fatty Acid Uptake ◽  
Chain Fatty Acid ◽  
Acid Uptake ◽  
Long Chain Fatty Acid ◽  
Long Chain

scholarly journals Decreased PEDF Promotes Hepatic Fatty Acid Uptake and Lipid Droplet Formation in the Pathogenesis of NAFLD

Nutrients ◽  
2020 ◽  
Vol 12 (1) ◽  
pp. 270
Author(s):  
Kuang-Tzu Huang ◽  
Kuang-Den Chen ◽  
Li-Wen Hsu ◽  
Chao-Pin Kung ◽  
Shu-Rong Li ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Lipid Droplet ◽  
Lipid Accumulation ◽  
Fatty Acid Uptake ◽  
Droplet Formation ◽  
Fatty Acid Transport ◽  
Acid Uptake ◽  
Sequencing Analysis ◽  
Simple Steatosis ◽  
Lipid Droplet Formation

Non-alcoholic fatty liver disease (NAFLD), the leading cause of chronic liver diseases worldwide, ranges from simple steatosis to steatohepatitis, with the risk for progressive fibrosis or even cirrhosis. While simple steatosis is a relatively benign condition, the buildup of toxic lipid metabolites can induce chronic inflammation, ultimately triggering disease progression. Pigment epithelium-derived factor (PEDF) is a secreted, multifunctional glycoprotein with lipid metabolic activities. PEDF promotes lipolysis through binding to adipose triglyceride lipase (ATGL), a key enzyme for triglyceride breakdown. In the current study, we aimed to delineate how changes in PEDF expression affect hepatic lipid accumulation. Our data revealed that hepatic PEDF was downregulated in a mouse NAFLD model. We further showed that decreased PEDF levels in hepatocytes in vitro resulted in elevated fatty acid uptake and lipid droplet formation, with concomitant upregulation of fatty acid transport proteins CD36 and fatty acid binding protein 1 (FABP1). RNA sequencing analysis of PEDF knocked down hepatocytes revealed an alteration in gene expression profile toward lipid accumulation. Additionally, decreased PEDF promotes mobilization of fatty acids, an observation distinct from blocking ATGL activity. Taken together, our data suggest that hepatic PEDF downregulation causes molecular changes that favor triglyceride accumulation, which may further lead to NAFLD progression.

Z-ligustilide and n-Butylidenephthalide Isolated from the Aerial Parts of Angelica tenuissima Inhibit Lipid Accumulation In Vitro and In Vivo

Planta Medica ◽  
2019 ◽  
Vol 85 (09/10) ◽  
pp. 719-728 ◽  
Author(s):  
Wonseok Lee ◽  
Hye Ryoung Koo ◽  
You-Jin Choi ◽  
Jin Gyu Choi ◽  
Myung Sook Oh ◽  
...  
Keyword(s):  
Oleic Acid ◽  
Fatty Acid ◽  
Lipid Accumulation ◽  
Hepg2 Cells ◽  
Target Genes ◽  
Regulatory Element ◽  
Fatty Acid Uptake ◽  
Acid Uptake

AbstractAbnormal lipid metabolism, such as increased fatty acid uptake and esterification, is associated with nonalcoholic fatty liver disease (NAFLD). The aqueous extract of the aerial part of Angelica tenuissima Nakai (ATX) inhibited high-fat diet–induced hepatic steatosis in mice as well as oleic acid–induced neutral lipid accumulation in HepG2 cells. ATX decreased the mRNA and protein levels of CD36 and diglyceride acyltransferase 2 (DGAT2), the maturation of sterol regulatory element-binding proteins (SREBP), and the expression of the lipogenic target genes fasn and scd1. The ATX components, Z-ligustilide and n-butylidenephthalide, inhibited the expression of FATP5 and DGAT2 and thus oleic acid–induced lipid accumulation in HepG2 cells. These results suggest that ATX and its active components Z-ligustilide and n-butylidenephthalide inhibit fatty acid uptake and esterification in mice and have potential as therapeutics for NAFLD.

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