scholarly journals Regulation of lipid droplet and membrane biogenesis by the acidic tail of the phosphatidate phosphatase Pah1p

2013 ◽  
Vol 24 (13) ◽  
pp. 2124-2133 ◽  
Author(s):  
Eleftherios Karanasios ◽  
Antonio Daniel Barbosa ◽  
Hiroshi Sembongi ◽  
Muriel Mari ◽  
Gil-Soo Han ◽  
...  
Keyword(s):  
Gene Expression ◽  
Lipid Droplet ◽  
Lipid Droplets ◽  
Important Determinant ◽  
Dependent Manner ◽  
Membrane Biogenesis ◽  
Phosphatidate Phosphatase ◽  
Evolutionarily Conserved ◽  
Important Regulator ◽  
Carboxy Terminal

Lipins are evolutionarily conserved phosphatidate phosphatases that perform key functions in phospholipid, triglyceride, and membrane biogenesis. Translocation of lipins on membranes requires their dephosphorylation by the Nem1p-Spo7p transmembrane phosphatase complex through a poorly understood mechanism. Here we identify the carboxy-terminal acidic tail of the yeast lipin Pah1p as an important regulator of this step. Deletion or mutations of the tail disrupt binding of Pah1p to the Nem1p-Spo7p complex and Pah1p membrane translocation. Overexpression of Nem1p-Spo7p drives the recruitment of Pah1p in the vicinity of lipid droplets in an acidic tail–dependent manner and induces lipid droplet biogenesis. Genetic analysis shows that the acidic tail is essential for the Nem1p-Spo7p–dependent activation of Pah1p but not for the function of Pah1p itself once it is dephosphorylated. Loss of the tail disrupts nuclear structure, INO1 gene expression, and triglyceride synthesis. Similar acidic sequences are present in the carboxy-terminal ends of all yeast lipin orthologues. We propose that acidic tail–dependent binding and dephosphorylation of Pah1p by the Nem1p-Spo7p complex is an important determinant of its function in lipid and membrane biogenesis.

scholarly journals Dehydroepiandrosterone Reduced Lipid Droplet Accumulation via Inhibiting Cell Proliferation and Improving Mitochondrial Function in Primary Chicken Hepatocytes

2018 ◽  
pp. 443-456
Author(s):  
L.-L. LI ◽  
D. WANG ◽  
C.-Y. GE ◽  
L. YU ◽  
J.-L. ZHAO ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Lipid Droplet ◽  
Mitochondrial Function ◽  
Mitochondrial Membrane ◽  
Lipid Droplets ◽  
Dependent Manner ◽  
Mitochondrial Membrane Permeability ◽  
Cyclin Dependent Kinases ◽  
Dhea Treatment ◽  
Dose Dependent

Dehydroepiandrosterone (DHEA) possesses fat-reducing effect, while little information is available on whether DHEA regulates cell proliferation and mitochondrial function, which would, in turn, affect lipid droplet accumulation in the broiler. In the present study, the lipid droplet accumulation, cell proliferation, cell cycle and mitochondrial membrane potential were analysis in primary chicken hepatocytes after DHEA treated. The results showed that total area and counts of lipid droplets were significantly decreased in hepatocytes treated with DHEA. The cell viability was significantly increased, while cell proliferation was significantly inhibited in a dose dependent manner in primary chicken hepatocytes after DHEA treated. DHEA treatment significantly increased the cell population in S phase and decreased the population in G2/M in primary chicken hepatocytes. Meanwhile, the cyclin A and cyclin-dependent kinases 2 (CDK2) mRNA abundance were significantly decreased in hepatocytes after DHEA treated. No significant differences were observed in the number of mitochondria, while the mitochondrial membrane permeability and succinate dehydrogenase (SDH) activity were significantly increased in hepatocytes after DHEA treated. In conclusion, our results demonstrated that DHEA reduced lipid droplet accumulation by inhibiting hepatocytes proliferation and enhancing mitochondrial function in primary chicken hepatocytes.

scholarly journals C/EBPγ Suppresses Senescence and Inflammatory Gene Expression by Heterodimerizing with C/EBPβ

2013 ◽  
Vol 33 (16) ◽  
pp. 3242-3258 ◽  
Author(s):  
Christopher J. Huggins ◽  
Radek Malik ◽  
Sook Lee ◽  
Jacqueline Salotti ◽  
Sara Thomas ◽  
...  
Keyword(s):  
Gene Expression ◽  
Lung Tumor ◽  
Gene Signature ◽  
Dependent Manner ◽  
Inflammatory Gene Expression ◽  
Important Regulator ◽  
Proinflammatory Gene ◽  
Covalently Linked ◽  
Nih 3T3 ◽  
Oncogenic Stress

C/EBPβ is an important regulator of oncogene-induced senescence (OIS). Here, we show that C/EBPγ, a heterodimeric partner of C/EBPβ whose biological functions are not well understood, inhibits cellular senescence.Cebpg−/−mouse embryonic fibroblasts (MEFs) proliferated poorly, entered senescence prematurely, and expressed a proinflammatory gene signature, including elevated levels of senescence-associated secretory phenotype (SASP) genes whose induction by oncogenic stress requires C/EBPβ. The senescence-suppressing activity of C/EBPγ required its ability to heterodimerize with C/EBPβ. Covalently linked C/EBPβ homodimers (β∼β) inhibited the proliferation and tumorigenicity of RasV12-transformed NIH 3T3 cells, activated SASP gene expression, and recruited the CBP coactivator in a Ras-dependent manner, whereas γ∼β heterodimers lacked these capabilities and efficiently rescued proliferation ofCebpg−/−MEFs. C/EBPβ depletion partially restored growth of C/EBPγ-deficient cells, indicating that the increased levels of C/EBPβ homodimers inCebpg−/−MEFs inhibit proliferation. The proliferative functions of C/EBPγ are not restricted to fibroblasts, as hematopoietic progenitors fromCebpg−/−bone marrow also displayed impaired growth. Furthermore, highCEBPGexpression correlated with poorer clinical prognoses in several human cancers, and C/EBPγ depletion decreased proliferation and induced senescence in lung tumor cells. Our findings demonstrate that C/EBPγ neutralizes the cytostatic activity of C/EBPβ through heterodimerization, which prevents senescence and suppresses basal transcription of SASP genes.

scholarly journals Lipid droplet evolution gives insight into polyaneuploid cancer cell lipid droplet functions

2021 ◽  
Vol 38 (11) ◽  
Author(s):  
Laurie G. Kostecka ◽  
Kenneth J. Pienta ◽  
Sarah R. Amend
Keyword(s):  
Cancer Cells ◽  
Cancer Cell ◽  
Lipid Droplet ◽  
Lipid Droplets ◽  
Chemotherapy Resistance ◽  
Tumor Aggressiveness ◽  
Evolutionarily Conserved ◽  
Energy Stores ◽  
Insight Into ◽  
Transitory State

AbstractLipid droplets (LDs) are found throughout all phyla across the tree of life. Originating as pure energy stores in the most basic organisms, LDs have evolved to fill various roles as regulators of lipid metabolism, signaling, and trafficking. LDs have been noted in cancer cells and have shown to increase tumor aggressiveness and chemotherapy resistance. A certain transitory state of cancer cell, the polyaneuploid cancer cell (PACC), appears to have higher LD levels than the cancer cell from which they are derived. PACCs are postulated to be the mediators of metastasis and resistance in many different cancers. Utilizing the evolutionarily conserved roles of LDs to protect from cellular lipotoxicity allows PACCs to survive otherwise lethal stressors. By better understanding how LDs have evolved throughout different phyla we will identify opportunities to target LDs in PACCs to increase therapeutic efficiency in cancer cells.

scholarly journals The FATP1–DGAT2 complex facilitates lipid droplet expansion at the ER–lipid droplet interface

2012 ◽  
Vol 198 (5) ◽  
pp. 895-911 ◽  
Author(s):  
Ningyi Xu ◽  
Shaobing O. Zhang ◽  
Ronald A. Cole ◽  
Sean A. McKinney ◽  
Fengli Guo ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Endoplasmic Reticulum ◽  
Lipid Droplet ◽  
Mammalian Cells ◽  
Lipid Droplets ◽  
Molecular Mechanisms ◽  
Diacylglycerol Acyltransferase ◽  
Present Evidence ◽  
Evolutionarily Conserved ◽  
Subcellular Level

At the subcellular level, fat storage is confined to the evolutionarily conserved compartments termed lipid droplets (LDs), which are closely associated with the endoplasmic reticulum (ER). However, the molecular mechanisms that enable ER–LD interaction and facilitate neutral lipid loading into LDs are poorly understood. In this paper, we present evidence that FATP1/acyl-CoA synthetase and DGAT2/diacylglycerol acyltransferase are components of a triglyceride synthesis complex that facilitates LD expansion. A loss of FATP1 or DGAT2 function blocked LD expansion in Caenorhabditis elegans. FATP1 preferentially associated with DGAT2, and they acted synergistically to promote LD expansion in mammalian cells. Live imaging indicated that FATP1 and DGAT2 are ER and LD resident proteins, respectively, and electron microscopy revealed FATP1 and DGAT2 foci close to the LD surface. Furthermore, DGAT2 that was retained in the ER failed to support LD expansion. We propose that the evolutionarily conserved FATP1–DGAT2 complex acts at the ER–LD interface and couples the synthesis and deposition of triglycerides into LDs both physically and functionally.

Thyroid Hormone Deficiency Modifies Hepatic Lipid Droplet Morphology and Molecular Properties in Lithogenic-Diet Supplemented Mice

2021 ◽  
Author(s):  
Irina Kube ◽  
Holger Jastrow ◽  
Dagmar Führer ◽  
Denise Zwanziger
Keyword(s):  
Gene Expression ◽  
Thyroid Hormone ◽  
Lipid Droplet ◽  
Lipid Droplets ◽  
Molecular Properties ◽  
Hormone Deficiency ◽  
Hepatic Lipid ◽  
Lithogenic Diet ◽  
Associated Proteins ◽  
Droplet Morphology

Abstract Objective Thyroid hormones have been associated with a hepatic lipid lowering effect and thyroid function has been shown to play a substantial role in development of non-alcoholic fatty liver disease. Hepatic lipid droplets differ in the number, size and molecular properties depending on metabolic state or pathological condition. However, in how far thyroid hormone deficiency affects hepatic lipid droplet morphology and molecular properties is still poorly understood. Therefore, we performed a study in mice using a lithogenic diet model of steatohepatitis and modulated the thyroid hormone status. Methods Male and female three months old C57BL/6 mice were divided into a euthyroid (control), a lithogenic (litho) and a lithogenic+thyroid hormone deficient (litho+hypo) group and treated for six weeks. Hepatic transmission electron microscopy and gene expression analysis of lipid-droplet associated proteins were performed. Results Increased mean diameters of hepatic lipid droplets and a shift towards raised electron-density in lipid droplets was observed under thyroid hormone deficiency. Furthermore thyroid hormone deficiency altered hepatic expression of genes involved in lipophagy and triacylglycerol mobilization. Interestingly, while the impact of thyroid hormone deficiency on lipid droplet morphology seems to be sex-independent, hepatic lipid droplet-associated gene expression differed significantly between both sexes. Conclusion This study demonstrates that thyroid hormone deficiency alters hepatic lipid droplet morphology and hepatic gene expression of lipid droplet-associated proteins in a lithogenic diet mouse model of steatohepatitis.

Mechanisms of lipid droplet biogenesis

2019 ◽  
Vol 476 (13) ◽  
pp. 1929-1942 ◽  
Author(s):  
Kent D. Chapman ◽  
Mina Aziz ◽  
John M. Dyer ◽  
Robert T. Mullen
Keyword(s):  
Endoplasmic Reticulum ◽  
Lipid Droplet ◽  
Lipid Droplets ◽  
Neutral Lipids ◽  
Steryl Esters ◽  
Evolutionarily Conserved ◽  
Compare And Contrast ◽  
In Cells

Abstract Lipid droplets (LDs) are organelles that compartmentalize nonbilayer-forming lipids in the aqueous cytoplasm of cells. They are ubiquitous in most organisms, including in animals, protists, plants and microorganisms. In eukaryotes, LDs are believed to be derived by a budding and scission process from the surface of the endoplasmic reticulum, and this occurs concomitantly with the accumulation of neutral lipids, most often triacylglycerols and steryl esters. Overall, the mechanisms underlying LD biogenesis are difficult to generalize, in part because of the involvement of different sets of both evolutionarily conserved and organism-specific LD-packaging proteins. Here, we briefly compare and contrast these proteins and the allied processes responsible for LD biogenesis in cells of animals, yeasts and plants.

A snapshot of Snf2 enzymes in fission yeast

2013 ◽  
Vol 41 (6) ◽  
pp. 1640-1647 ◽  
Author(s):  
Punit Prasad ◽  
Karl Ekwall
Keyword(s):  
Gene Expression ◽  
Fission Yeast ◽  
Molecular Mechanisms ◽  
Dna Recombination ◽  
Chromatin Remodelling ◽  
Present Review ◽  
Dependent Manner ◽  
Evolutionarily Conserved ◽  
Eukaryotic Chromatin ◽  
Heterochromatin Structure

Eukaryotic chromatin is remodelled by the evolutionarily conserved Snf2 family of enzymes in an ATP-dependent manner. Several Snf2 enzymes are part of CRCs (chromatin remodelling complexes). In the present review we focus our attention on the functions of Snf2 enzymes and CRCs in fission yeast. We discuss their molecular mechanisms and roles and in regulating gene expression, DNA recombination, euchromatin and heterochromatin structure.

Abstract 16082: Plin2 Attenuates Cardiomyocyte Lipotoxicity

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Felix-Antoine Berube-Simard ◽  
Taha Haffar ◽  
Nicolas Bousette
Keyword(s):  
Gene Expression ◽  
Fatty Acid ◽  
Lipid Droplet ◽  
Lipid Droplets ◽  
Target Genes ◽  
Binding Protein ◽  
Neonatal Cardiomyocytes ◽  
Mediated Effects ◽  
The Subject ◽  
Rate Limiting

Diabetic cardiomyopathy is associated with excess lipid accumulation in the heart. We previously showed that oleate, a non-toxic mono-unsaturated fatty acid causes the formation of abundant lipid droplets in cardiomyocytes that were lined with Plin2, an important lipid droplet binding protein. In contrast, palmitate, a toxic saturated fatty acid, led to the formation of aberrant lipid droplets which lacked Plin2 immunoreactivity. Hypothesis: We hypothesized that Plin2 overexpression may protect against palmitate mediated lipotoxicity. Methods: We overexpressed and silenced Plin2 in rat neonatal cardiomyocytes (NCMs) by LentiVector mediated overexpression of Plin2 cDNA and shRNAs, respectively. We treated these NCMs with bovine serum albumin (51μM, vehicle control), 100-300μM oleate, or 100-300μM palmitate for 4-24 hours. We evaluated viability with the propidium iodide exclusion assay and measured gene expression by qRT-PCR. Results: Plin2 overexpression protected NCMs from the lipotoxic effects of palmitate. Conversely, silencing of Plin2 sensitized NCMs to the effects of palmitate and caused oleate, which is normally non-toxic, to induce cell death in NCMs. Interestingly, we found that Plin2 overexpression had a marked stimulatory effect on several PPAR target genes including Carnitine palmitoyl transferase 1b (Cpt1b), the rate limiting enzyme in β-oxidation. In contrast, Plin2 silencing led to a significant decrease in oleate induced expression of PPAR target genes, including Cpt1b. Conclusion: Here we showed that overexpression of Plin2, a key lipid droplet binding protein protected against lipotoxicity, while silencing it caused lipotoxicity. We show that this may be due to alterations in lipid metabolism, since Plin2 overexpression led to increased expression of key β-oxidation genes. This is important because we have previously shown that palmitate impairs β-oxidation capacity in cardiomyocytes. Therefore enhancing β-oxidation may attenuate lipotoxicity by limiting the build-up of lipid metabolites. The mechanism of Plin2 mediated effects on PPAR target gene expression, as well as the effect on lipid droplet formation are the subject of on-going studies.

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