scholarly journals The incorporation of radioactive fatty acids into the phospholipids of nerve-cell-body membranes in vivo. Evidence for highly labelled neuronal nuclei

1980 ◽  
Vol 188 (1) ◽  
pp. 153-161 ◽  
Author(s):  
R. Roy Baker ◽  
Huu-yi Chang
Keyword(s):  
Fatty Acid ◽  
Nerve Cell ◽  
Cell Body ◽  
High Speed ◽  
De Novo ◽  
Nerve Cell Body ◽  
Double Labelling ◽  
Nuclear Fraction ◽  
Mitochondrial Fractions

1. Nerve cell bodies were isolated in bulk from cerebral cortices of 15 day-old rabbits after intrathecal injections of [3H]plamitate, [3H]oleate or [3H]arachidonate and [14C]glycerol. 2. Nuclear, microsomal and two mitochondrial fractions were isolated from homogenates of the radioactively labelled nerve cell bodies by using differential and discontinuous-gradient centrifugation. 3. After 7.5min in vivo, a high percentage (>80%) of the total 3H-labelled fatty acid radioactivity was found in the membrane fractions of the nerve cell bodies, whereas after 60min in vivo 50% of the total [14C]glycerol radioactivity was found in the high-speed supernatant. 4. The specific radioactivities of phosphatidylcholine, phosphatidylethanolamine and phosphatidylinositol, and the radioactivity in neutral lipid and non-esterified fatty acid fractions were determined in the four subfractions, as were the distributions of several marker enzymes and nucleates. 5. With respect of 3H-labelled fatty acid, the phospholipids of the nuclear fraction had the highest specific radioactivities of the four subfractions. However, for [14C]glycerol labelling, generally the 14C specific radioactivities for individual phospholipids were comparable in the four subfractions. This latter observation suggests transport of phospholipids synthesized de novo between membranes of the nerve cell body. 6. Double-labelling experiments demonstrated that individual phospholipids and the combined neutral lipids of the nuclear fraction had higher labelling ratios of 3H-labelled fatty acid/[14C]glycerol than did the corresponding lipids of the microsomal or mitochondrial fractions. 7. On the basis of the labelling results and the marker studies, it is proposed that it is indeed the nuclei of the nuclear fraction that have these lipids highly labelled with 3H-labelled fatty acid, and the existence of nuclear acyl transferases that are responsible for this fatty acid incorporation is suggested.

scholarly journals Targeting de novo lipogenesis and the Lands cycle induces ferroptosis in KRAS-mutant lung cancer

2021 ◽  
Author(s):  
Caterina Bartolacci ◽  
Cristina Andreani ◽  
Goncalo Dias do Vale ◽  
Stefano Berto ◽  
Margherita Melegari ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Fatty Acid ◽  
Metabolic Networks ◽  
Fatty Acid Synthase ◽  
De Novo ◽  
Genetically Engineered ◽  
De Novo Lipogenesis ◽  
Main Process

Mutant KRAS (KM) is the most common oncogene in lung cancer (LC). KM regulates several metabolic networks, but their role in tumorigenesis is still not sufficiently characterized to be exploited in cancer therapy. To identify metabolic networks specifically deregulated in KMLC, we characterized the lipidome of genetically engineered LC mice, cell lines, patient derived xenografts and primary human samples. We also determined that KMLC, but not EGFR-mutant (EGFR-MUT) LC, is enriched in triacylglycerides (TAG) and phosphatidylcholines (PC). We also found that KM upregulates fatty acid synthase (FASN), a rate-limiting enzyme in fatty acid (FA) synthesis promoting the synthesis of palmitate and PC. We determined that FASN is specifically required for the viability of KMLC, but not of LC harboring EGFR-MUT or wild type KRAS. Functional experiments revealed that FASN inhibition leads to ferroptosis, a reactive oxygen species (ROS)-and iron-dependent cell death. Consistently, lipidomic analysis demonstrated that FASN inhibition in KMLC leads to accumulation of PC with polyunsaturated FA (PUFA) chains, which are the substrate of ferroptosis. Integrating lipidomic, transcriptome and functional analyses, we demonstrated that FASN provides saturated (SFA) and monounsaturated FA (MUFA) that feed the Lands cycle, the main process remodeling oxidized phospholipids (PL), such as PC. Accordingly, either inhibition of FASN or suppression of the Lands cycle enzymes PLA2 and LPCAT3, promotes the intracellular accumulation of lipid peroxides and ferroptosis in KMLC both in vitro and in vivo. Our work supports a model whereby the high oxidative stress caused by KM dictates a dependency on newly synthesized FA to repair oxidated phospholipids, establishing a targetable vulnerability. These results connect KM oncogenic signaling, FASN induction and ferroptosis, indicating that FASN inhibitors already in clinical trial in KMLC patients (NCT03808558) may be rapidly deployed as therapy for KMLC.

Fatty-acid synthase activity and mRNA level in hypertrophic type II cells from silica-treated rats

1994 ◽  
Vol 267 (2) ◽  
pp. L128-L136
Author(s):  
J. Rami ◽  
W. Stenzel ◽  
S. M. Sasic ◽  
C. Puel-M'Rini ◽  
J. P. Besombes ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Synthase ◽  
Fatty Acid Biosynthesis ◽  
De Novo ◽  
Mrna Level ◽  
Type Ii Cells ◽  
Mrna Levels ◽  
Type Ii ◽  
Maximum Increase

Silica instillation causes a massive increase in lung surfactant. Two populations of type II pneumocytes can be isolated from rats administered silica by intratracheal injection: type IIA cells similar to type II cells from normal rats and type IIB cells, which are larger and contain elevated levels of surfactant protein A and phospholipid. Activities of choline-phosphate cytidylyltransferase, a rate-regulatory enzyme in phosphatidylcholine biosynthesis, and fatty-acid synthase (FAS) are increased in type IIB cells isolated from rats 14 days after silica injection. In the present study, we examined the increase in FAS and cytidylyltransferase activities in type IIB cells as a function of time after silica administration. FAS activity increased rapidly, was approximately threefold elevated 1 day after silica administration and has reached close to the maximum increase by 3 days. Cytidylyltransferase activity was not increased on day 1, was significantly increased on day 3 but was not maximally increased until day 7. Inhibition of de novo fatty-acid biosynthesis, by in vivo injection of hydroxycitric acid and inclusion of agaric acid in the type II cell culture medium, abolished the increase in cytidylyltransferase activity on day 3 but not FAS and had no effect on activities of two other enzymes of phospholipid synthesis. FAS mRNA levels were not increased in type IIB cells isolated 1-14 days after silica injection. These data show that the increase in FAS activity in type IIB cells is an early response to silica, that it mediates the increase in cytidylyltransferase activity, and that it is not due to enhanced FAS gene expression.

scholarly journals The rate of diffusion of Ca2+ and Ba2+ in a nerve cell body

1985 ◽  
Vol 47 (5) ◽  
pp. 735-738 ◽  
Author(s):  
E. Nasi ◽  
D. Tillotson
Keyword(s):  
Nerve Cell ◽  
Cell Body ◽  
Nerve Cell Body

scholarly journals USP22-dependent accumulation of lipidomes drives hepatocellular carcinoma progression by stabilizing PPARγ

2020 ◽  
Author(s):  
Zhen Ning ◽  
Xin Guo ◽  
Xiaolong Liu ◽  
Chang Lu ◽  
Aman Wang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Fatty Acid ◽  
Molecular Mechanism ◽  
Fatty Acid Synthesis ◽  
De Novo ◽  
Acid Synthesis ◽  
Specific Protease ◽  
Pparγ Expression

Abstract Elevated de novo lipogenesis (DNL) is considered to be a crucial factor in hepatocellular carcinoma (HCC) development. However, the molecular mechanism for its occurrence in HCC is still unclear. Herein, we identified ubiquitin-specific protease 22 (USP22) as a key regulator for de novo fatty acid synthesis, which directly interacts with, deubiquitinates and stabilizes PPARγ through K48-linked deubiquitination, and in turn, this stabilization increases ACC and ACLY transcription. In addition, we found that USP22 promoted the de novo synthesis of fatty acid labeling from glucose tracers. USP22-dysregulated de novo fatty acid synthesis contributes to HCC progression, but USP22 was functionality suppressed by inhibiting the expression of PPARγ, ACLY, or ACC in in vitro cell proliferation and in vivo tumorigenesis experiments. In HCC, USP22 expression positively correlates with PPARγ expression, and simultaneously, high expression of USP22 and PPARγ or USP22, ACC and ACLY is associated with a poor prognosis. Taken together, we identified a previously undescribed USP22-regulated lipogenesis molecular mechanism that involves the PPARγ-ACLY/ACC axis in HCC tumorigenesis and provide a rationale for therapeutic targeting of lipogenesis via USP22 inhibition.

scholarly journals Engineering nature for gaseous hydrocarbon production

2020 ◽  
Vol 19 (1) ◽  
Author(s):  
Mohamed Amer ◽  
Helen Toogood ◽  
Nigel S. Scrutton
Keyword(s):  
Fatty Acid ◽  
Fossil Fuels ◽  
Fatty Acid Biosynthesis ◽  
De Novo ◽  
Gas Production ◽  
Single Step ◽  
Short Chain ◽  
Gaseous Hydrocarbon ◽  
Gas Formation

AbstractThe development of sustainable routes to the bio-manufacture of gaseous hydrocarbons will contribute widely to future energy needs. Their realisation would contribute towards minimising over-reliance on fossil fuels, improving air quality, reducing carbon footprints and enhancing overall energy security. Alkane gases (propane, butane and isobutane) are efficient and clean-burning fuels. They are established globally within the transportation industry and are used for domestic heating and cooking, non-greenhouse gas refrigerants and as aerosol propellants. As no natural biosynthetic routes to short chain alkanes have been discovered, de novo pathways have been engineered. These pathways incorporate one of two enzymes, either aldehyde deformylating oxygenase or fatty acid photodecarboxylase, to catalyse the final step that leads to gas formation. These new pathways are derived from established routes of fatty acid biosynthesis, reverse β-oxidation for butanol production, valine biosynthesis and amino acid degradation. Single-step production of alkane gases in vivo is also possible, where one recombinant biocatalyst can catalyse gas formation from exogenously supplied short-chain fatty acid precursors. This review explores current progress in bio-alkane gas production, and highlights the potential for implementation of scalable and sustainable commercial bioproduction hubs.

scholarly journals Localization of chloroplastic fatty acid synthesis de novo in the stroma

1985 ◽  
Vol 226 (2) ◽  
pp. 551-556 ◽  
Author(s):  
K A Walker ◽  
J L Harwood
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Synthesis ◽  
High Speed ◽  
De Novo ◽  
Fatty Acid Synthetase ◽  
Acid Synthesis ◽  
Synthetic Activity ◽  
Bisphosphate Carboxylase ◽  
Osmotic Lysis ◽  
Almost All

The synthesis of fatty acids de novo from [2-14C]malonyl-CoA was studied in fractions from lettuce (Lactuca sativa) and pea (Pisum sativum) chloroplasts. When lettuce chloroplasts were subjected to osmotic lysis, disintegration through a Yeda press and high-speed centrifugation, essentially all of the fatty-acid-synthetic activity was found to be soluble. The distribution of the activity in various chloroplast fractions was similar to that of soluble marker enzymes such as ribulose-1,5-bisphosphate carboxylase and NADP+-linked glyceraldehyde-3-phosphate dehydrogenase. Marked differences were apparent in the quality of products from fatty acid synthesis de novo in the various fractions of chloroplasts. Thus soluble fractions produced predominantly stearate, whereas those containing membranes produced a greater proportion of palmitate. In pea chloroplasts, osmotic lysis released almost all of the fatty acid synthetase into the stromal fraction. In this instance, no major alterations in the products of fatty acid synthesis were observed. The fatty-acid-synthetic activity of the stromal fraction was still soluble after prolonged ultracentrifugation. The results show clearly the soluble nature of fatty acid synthesis de novo in lettuce and pea chloroplasts. Thus fatty acid synthesis measured in microsomal fractions from such plant tissues is not due to the presence of chloroplastic membranes.

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