scholarly journals HILPDA Regulates Lipid Metabolism, Lipid Droplet Abundance, and Response to Microenvironmental Stress in Solid Tumors

2019 ◽  
Vol 17 (10) ◽  
pp. 2089-2101 ◽  
Author(s):  
Matthew J. VandeKopple ◽  
Jinghai Wu ◽  
Erich N. Auer ◽  
Amato J. Giaccia ◽  
Nicholas C. Denko ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Solid Tumors ◽  
Lipid Droplet ◽  
Microenvironmental Stress

scholarly journals A conserved family of proteins facilitates nascent lipid droplet budding from the ER

2015 ◽  
Vol 211 (2) ◽  
pp. 261-271 ◽  
Author(s):  
Vineet Choudhary ◽  
Namrata Ojha ◽  
Andy Golden ◽  
William A. Prinz
Keyword(s):  
Electron Microscopy ◽  
Endoplasmic Reticulum ◽  
Lipid Metabolism ◽  
Caenorhabditis Elegans ◽  
Lipid Droplet ◽  
Lipid Droplets ◽  
De Novo ◽  
Fat Storage ◽  
Higher Eukaryotes ◽  
Er Membrane

Lipid droplets (LDs) are found in all cells and play critical roles in lipid metabolism. De novo LD biogenesis occurs in the endoplasmic reticulum (ER) but is not well understood. We imaged early stages of LD biogenesis using electron microscopy and found that nascent LDs form lens-like structures that are in the ER membrane, raising the question of how these nascent LDs bud from the ER as they grow. We found that a conserved family of proteins, fat storage-inducing transmembrane (FIT) proteins, is required for proper budding of LDs from the ER. Elimination or reduction of FIT proteins in yeast and higher eukaryotes causes LDs to remain in the ER membrane. Deletion of the single FIT protein in Caenorhabditis elegans is lethal, suggesting that LD budding is an essential process in this organism. Our findings indicated that FIT proteins are necessary to promote budding of nascent LDs from the ER.

scholarly journals Multifunctional pyrazoline based AIEgens: real-time tracking and specific protein “fishing” of lipid droplets

2019 ◽  
Vol 10 (39) ◽  
pp. 9009-9016 ◽  
Author(s):  
Na Zhao ◽  
Yan Li ◽  
Weiyao Yang ◽  
Jiabao Zhuang ◽  
Yue Li ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Real Time ◽  
Intracellular Ph ◽  
Lipid Droplet ◽  
Lipid Droplets ◽  
Specific Protein ◽  
Related Protein ◽  
Dual Color ◽  
Real Time Tracking

A series of multifunctional pyrazoline based AIEgens were developed for real-time tracking of lipid metabolism, reversibly monitoring intracellular pH in dual-color mode and specific labeling of lipid droplet related protein.

scholarly journals Lipid-Lowering Effects of Lotus Leaf Alcoholic Extract on Serum, Hepatopancreas, and Muscle of Juvenile Grass Carp via Gene Expression

2020 ◽  
Vol 11 ◽  
Author(s):  
Junpeng Yao ◽  
Pengcheng Hu ◽  
Yanhong Zhu ◽  
Yingyan Xu ◽  
Qingsong Tan ◽  
...  
Keyword(s):  
Gene Expression ◽  
Fatty Acid ◽  
Lipid Metabolism ◽  
Lipid Droplet ◽  
Grass Carp ◽  
Lipid Lowering ◽  
Lipid Deposition ◽  
Alcoholic Extract ◽  
Mrna Levels ◽  
Lotus Leaf

Compared with wild grass carp (Ctenopharyngodon idellus), intensively cultured fish displayed disordered lipid metabolism, showing excess lipid deposition in the hepatopancreas and muscle. Lotus leaf prevents fat accumulation in humans and may have similar effects on fish. This study explored the regulatory mechanisms by which the dietary addition of an alcoholic extract of lotus leaf (AELL) reduced lipid deposition in the hepatopancreas and muscle of juvenile grass carp. The fish (average initial weight: 34.00 ± 0.40 g) were fed four experimental diets containing different AELL levels (0, 0.07, 0.14, and 0.21%) for 8 weeks. Serum components, lipid droplet size, triacylglycerol (TAG) content, enzymatic activities, and mRNA levels of genes related to lipid metabolism in the hepatopancreas and muscle were analyzed. The results show that dietary AELL supplementation significantly reduced the TAG content and lipid droplet area in the histological sections as well as the fatty acid synthase (FAS) activity in both the hepatopancreas and muscle but enhanced the activities of lipoprotein lipase (LPL) and carnitine palmitoyltransferase I (CPT1) in both tissues. In addition, dietary AELL supplementation decreased the mRNA expression of genes involved in fatty acid uptake (cd36, fatp1/fatp4/fatp6, fabp10/fabp11, acsl1/acsl4) and de novo lipid synthesis (pgd, g6pd, and fasn) as well as the transcription factors pparg and srebf1 in the hepatopancreas and muscle but increased the mRNA levels of genes relating to lipid catabolism (cpt1a, lipe, pnpla2, lpl), lipid transportation (apob), and the transcription factor ppara in both tissues. In conclusion, dietary AELL supplementation reduced lipid accumulation in the hepatopancreas and muscle by affecting the gene expression of proteins with known effects on lipid metabolism in juvenile grass carp.

scholarly journals Perilipin 5 S155 phosphorylation by PKA is required for the control of hepatic lipid metabolism and glycemic control

2020 ◽  
pp. jlr.RA120001126
Author(s):  
Stacey N Keenan ◽  
William DeNardo ◽  
Jieqiong Lou ◽  
Ralf B. Schittenhelm ◽  
Magdalene K. Montgomery ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Lipid Metabolism ◽  
Glycemic Control ◽  
Fatty Acid Oxidation ◽  
Lipid Droplet ◽  
Critical Role ◽  
The Body ◽  
Acid Oxidation ◽  
Hepatic Lipid Metabolism ◽  
Hepatic Lipid

Perilipin (PLIN) 5 is a lipid droplet-associated protein that coordinates intracellular lipolysis in highly oxidative tissues and is thought to regulate lipid metabolism in response to phosphorylation by protein kinase A (PKA). We sought to identify PKA phosphorylation sites in PLIN5 and assess their functional relevance in cultured cells and the livers of mice. We detected phosphorylation on S155, S161 and S163 of recombinant PLIN5 by PKA in vitro and identified S155 as a functionally important site for lipid metabolism. Expression of phosphorylation-defective PLIN5 S155A in Plin5 null cells resulted in decreased rates of lipolysis and triglyceride-derived fatty acid oxidation compared with cells expressing wildtype PLIN5. These differences in lipid metabolism were not associated with differences in the cellular distribution of PLIN5. Rather, FLIM-FRET analysis of protein-protein interactions showed that PLIN5 S155 phosphorylation regulates PLIN5 interaction with adipose triglyceride lipase (ATGL) at the lipid droplet, but not with the co-activator of ATGL, α-β hydrolase domain-containing 5 (ABHD5). Re-expression of PLIN5 S155A in the liver of Plin5 liver-specific null mice reduced lipolysis when compared to mice with wildtype PLIN5 re-expression, but was not associated with other changes in hepatic lipid metabolism, such as fatty acid oxidation, de novo lipogenesis and triglyceride secretion. Furthermore, glycemic control was impaired in mice with expression of PLIN5 S155A compared with mice expressing PLIN5. Together, these studies demonstrate that PLIN5 S155 is required for PKA-mediated lipolysis and builds on the body of evidence demonstrating a critical role for PLIN5 in coordinating lipid and glucose metabolism

scholarly journals STEM-26. ALTERED LIPID METABOLISM MARKS GLIOBLASTOMA STEM AND NON-STEM CELLS IN SEPARATE TUMOR NICHES

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi239-vi239
Author(s):  
Lisa Wallace ◽  
Anthony Gromovsky ◽  
James Hale ◽  
Arnon Knudsen ◽  
Briana Prager ◽  
...  
Keyword(s):  
Stem Cells ◽  
Lipid Metabolism ◽  
Lipid Droplet ◽  
Neutral Lipids ◽  
Cell Populations ◽  
Lower Grade ◽  
High Lipid ◽  
Lipid Species ◽  
Altered Lipid Metabolism ◽  
Altered Lipid

Abstract Clinical glioblastoma is marked by a strikingly heterogeneous mix of cell types, cellular metabolisms, and cellular microenvironments spread in different spatial locations throughout a tumor. We have created 3-dimensional organoid models that partially mimic the transition zone between nutrient-rich cellular tumor regions and nutrient-poor psuedopallisading and perinecrotic tumor zones. We found a dramatic disparity in lipid droplet presence between these regions with high lipid accumulation in the hypoxic organoid cores of a wide spectrum of patient derived specimens. This is accompanied by regionally restricted upregulation of HILPDA gene expression in the cores of our models, in clinical GBM specimens but not lower grade brain tumors, and localized specifically to pseudopallisading regions of patient tumors. We further show that lipid droplet accumulation overall marks perinecrotic and pseudopallisading regions in clinical GBM, indicating broadly altered lipid metabolism between these distinct cell populations. High lipid droplet accumulation is largely restricted to the non-stem cell populations of GBM organoids and sorted xenograft tumors whereas the stem cells are lipid-poor, suggesting lipid levels may not be simply a product of the microenvironment but also may be a reflection of cell state. We performed global lipidomic analysis on prospectively sorted stem and non-stem cells of multiple patient-derived models and found that GBM stem cells have comparatively decreased levels of neutral lipids, indicating a significant metabolic shift compared to non-stem cells from the same patient. Conversely, GBM stem cells have significantly increased levels of rare specific lipid species, and also display altered phospholipid synthesis and species specific alterations in phospholipid classes. Our findings suggest avenues for therapy by targeting the altered lipid metabolic pathways of these disparate tumor cell populations.

scholarly journals Seipin-Mediated Contacts as Gatekeepers of Lipid Flux at the Endoplasmic Reticulum–Lipid Droplet Nexus 

Contact ◽  
2020 ◽  
Vol 3 ◽  
pp. 251525642094582
Author(s):  
Veijo T. Salo ◽  
Maarit Hölttä-Vuori ◽  
Elina Ikonen
Keyword(s):  
Endoplasmic Reticulum ◽  
Lipid Metabolism ◽  
Recent Work ◽  
Lipid Droplet ◽  
Lipid Droplets ◽  
Intimate Relationship

Lipid droplets (LDs) are dynamic cellular hubs of lipid metabolism. While LDs contact a plethora of organelles, they have the most intimate relationship with the endoplasmic reticulum (ER). Indeed, LDs are initially assembled at specialized ER subdomains, and recent work has unraveled an increasing array of proteins regulating ER-LD contacts. Among these, seipin, a highly conserved lipodystrophy protein critical for LD growth and adipogenesis, deserves special attention. Here, we review recent insights into the role of seipin in LD biogenesis and as a regulator of ER-LD contacts. These studies have also highlighted the evolving concept of ER and LDs as a functional continuum for lipid partitioning and pinpointed a role for seipin at the ER-LD nexus in controlling lipid flux between these compartments.

scholarly journals CDKN2A/p16INK4a suppresses hepatic fatty acid oxidation through the AMPKα2-SIRT1-PPARα signaling pathway

2020 ◽  
Vol 295 (50) ◽  
pp. 17310-17322
Author(s):  
Yann Deleye ◽  
Alexia Karen Cotte ◽  
Sarah Anissa Hannou ◽  
Nathalie Hennuyer ◽  
Lucie Bernard ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Lipid Metabolism ◽  
Fatty Acid Oxidation ◽  
Lipid Droplet ◽  
Acid Oxidation ◽  
Hepatic Lipid Metabolism ◽  
Hepatic Lipid ◽  
Hepatic Fatty Acid Oxidation

In addition to their well-known role in the control of cellular proliferation and cancer, cell cycle regulators are increasingly identified as important metabolic modulators. Several GWAS have identified SNPs near CDKN2A, the locus encoding for p16INK4a (p16), associated with elevated risk for cardiovascular diseases and type-2 diabetes development, two pathologies associated with impaired hepatic lipid metabolism. Although p16 was recently shown to control hepatic glucose homeostasis, it is unknown whether p16 also controls hepatic lipid metabolism. Using a combination of in vivo and in vitro approaches, we found that p16 modulates fasting-induced hepatic fatty acid oxidation (FAO) and lipid droplet accumulation. In primary hepatocytes, p16-deficiency was associated with elevated expression of genes involved in fatty acid catabolism. These transcriptional changes led to increased FAO and were associated with enhanced activation of PPARα through a mechanism requiring the catalytic AMPKα2 subunit and SIRT1, two known activators of PPARα. By contrast, p16 overexpression was associated with triglyceride accumulation and increased lipid droplet numbers in vitro, and decreased ketogenesis and hepatic mitochondrial activity in vivo. Finally, gene expression analysis of liver samples from obese patients revealed a negative correlation between CDKN2A expression and PPARA and its target genes. Our findings demonstrate that p16 represses hepatic lipid catabolism during fasting and may thus participate in the preservation of metabolic flexibility.

TAMI-18. DIFFERENTIAL LIPID METABOLISM IN CANCER MICROENVIRONMENTS LEADS TO A REQUIREMENT FOR FATTY ACID DESATURASES FADS1 AND FADS2 IN GBM CANCER STEM CELL MAINTENANCE

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi201-vi202
Author(s):  
Sajina Shakya ◽  
Anthony D Gromovsky ◽  
James S Hale ◽  
Arnon M Knudsen ◽  
Briana Prager ◽  
...  
Keyword(s):  
Stem Cell ◽  
Fatty Acid ◽  
Lipid Metabolism ◽  
Cancer Stem Cell ◽  
Lipid Droplet ◽  
Neutral Lipids ◽  
Cell Activity ◽  
Cellular Heterogeneity ◽  
Fatty Acid Desaturases ◽  
Fatty Acid Production

Abstract Glioblastoma (GBM) is marked by cellular heterogeneity through microenvironments of a tumor, including metabolic heterogeneity. While altered cellular metabolism in cancer is well-known, how lipid metabolism is altered in different GBM microenvironmental conditions and cancer stem cell (CSC) states within a tumor remains an open question. We developed 3-dimensional GBM organoid models that mimic the transition zone between nutrient-rich cellular tumor and nutrient-poor psuedopalisading/perinecrotic tumor regions and performed spatially defined RNA-sequencing to investigate lipid metabolism. Spatial analysis revealed striking differences in metabolism between diverse cell populations from the same patient, with lipid enrichment in the hypoxic organoid cores and the pseudopalisading regions of patient tumors. This was accompanied by regionally restricted upregulation of lipid droplets and Hypoxia Inducible Lipid Droplet Associated gene expression in organoid cores and in the pseudopalisading regions of clinical GBM tumors. Using targeted lipidomic analysis, we assessed differences in acutely enriched CSC and non-CSCs from patient-derived models to explore the link between stem cell state and lipid metabolism. CSCs have low lipid droplet accumulation compared to non-CSCs in organoids and xenograft tumors, and prospectively sorted lipid-low GBM cells are functionally enriched for stem cell activity. This suggests lipid metabolism may not be simply a product of the microenvironment but also may be a reflection of cellular state. CSCs had decreased levels of major classes of neutral lipids compared to non-CSCs, but had significantly increased polyunsaturated fatty acid production due to increased expression of fatty acid desaturases FADS1 and FADS2. FADS1 and FADS2 expression are both essential to maintain CSC viability and self-renewal. Our data demonstrate that spatially and hierarchically distinct lipid metabolism phenotypes occur clinically in the majority of patients, can be recapitulated in laboratory models, and these altered lipid metabolic pathways may represent therapeutic targets for GBM.

scholarly journals C. elegans DBL-1/BMP Regulates Lipid Accumulation via Interaction with Insulin Signaling

2017 ◽  
Author(s):  
JF Clark ◽  
M Meade ◽  
G Ranepura ◽  
DH Hall ◽  
C Savage-Dunn
Keyword(s):  
Lipid Metabolism ◽  
Lipid Droplet ◽  
Lipid Accumulation ◽  
Metabolic Disorders ◽  
Bmp Signaling ◽  
Lipid Homeostasis ◽  
Metabolic Homeostasis ◽  
C Elegans ◽  
Lipid Droplet Size ◽  
Lipid Stores

AbstractMetabolic homeostasis is coordinately controlled by diverse inputs, which must be understood to combat metabolic disorders. Here we introduce DBL-1, the C. elegans BMP2/4 homolog, as a significant regulator of lipid homeostasis. We used neutral lipid staining and a lipid droplet marker to demonstrate that both increases and decreases in DBL-1/BMP signaling result in reduced lipid stores and lipid droplet count. We find that lipid droplet size, however, correlates positively with the level of DBL 1/BMP signaling. Regulation of lipid accumulation in the intestine occurs through non-cell-autonomous signaling, since expression of SMA-3, a Smad signal transducer, in the epidermis (hypodermis) is sufficient to rescue the loss of lipid accumulation. Finally, genetic evidence indicates that DBL-1/BMP functions upstream of Insulin/IGF-1 Signaling (IIS) in lipid metabolism. We conclude that BMP signaling regulates lipid metabolism in C. elegans through inter-organ signaling to IIS, shedding light on a less well-studied regulatory mechanism for metabolic homeostasis.

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