Rate Of Lipid Synthesis Research Articles

Hydrogen isotope fractionation is controlled by CO2 in coccolithophore lipids

Hydrogen isotope ratios (δ2H) represent an important natural tracer of metabolic processes, but quantitative models of processes controlling H-fractionation in aquatic photosynthetic organisms are lacking. Here, we elucidate the underlying physiological controls of 2H/1H fractionation in algal lipids by systematically manipulating temperature, light, and CO2(aq) in continuous cultures of the haptophyte Gephyrocapsa oceanica. We analyze the hydrogen isotope fractionation in alkenones (αalkenone), a class of acyl lipids specific to this species and other haptophyte algae. We find a strong decrease in the αalkenone with increasing CO2(aq) and confirm αalkenone correlates with temperature and light. Based on the known biosynthesis pathways, we develop a cellular model of the δ2H of algal acyl lipids to evaluate processes contributing to these controls on fractionation. Simulations show that longer residence times of NADPH in the chloroplast favor a greater exchange of NADPH with 2H-richer intracellular water, increasing αalkenone. Higher chloroplast CO2(aq) and temperature shorten NADPH residence time by enhancing the carbon fixation and lipid synthesis rates. The inverse correlation of αalkenone to CO2(aq) in our cultures suggests that carbon concentrating mechanisms (CCM) do not achieve a constant saturation of CO2 at the Rubisco site, but rather that chloroplast CO2 varies with external CO2(aq). The pervasive inverse correlation of αalkenone with CO2(aq) in the modern and preindustrial ocean also suggests that natural populations may not attain a constant saturation of Rubisco with the CCM. Rather than reconstructing growth water, αalkenone may be a powerful tool to elucidate the carbon limitation of photosynthesis.

The expression of genes encoding novel Sesame oleosin variants facilitates enhanced triacylglycerol accumulation in Arabidopsis leaves and seeds.

Triacylglycerols (TAG), accumulate within lipid droplets (LD), predominantly surrounded by OLEOSINs (OLE), that protect TAG from hydrolysis. We tested the hypothesis that identifying and removing degradation signals from OLE would promote its abundance, preventing TAG degradation and enhancing TAG accumulation. We tested whether mutating potential ubiquitin-conjugation sites in a previously reported improved Sesamum indicum OLE (SiO) variant, o3-3 Cys-OLE (SiCO herein), would stabilize it and increase its lipogenic potential. SiCOv1 was created by replacing all five lysines in SiCO with arginines. Separately, six cysteine residues within SiCO were deleted to create SiCOv2. SiCOv1 and SiCOv2 mutations were combined to create SiCOv3. Transient expression of SiCOv3 in Nicotiana benthamiana increased TAG by two-fold relative to SiCO. Constitutive expression of SiCOv3 or SiCOv5, containing the five predominant TAG-increasing mutations from SiCOv3, in Arabidopsis along with mouse DGAT2 (mD) increased TAG accumulation by 54% in leaves and 13% in seeds compared with control lines coexpressing SiCO and mD. Lipid synthesis rates increased, consistent with an increase in lipid sink strength that sequesters newly synthesized TAG, thereby relieving the constitutive BADC-dependent inhibition of ACCase reported for WT Arabidopsis. These OLE variants represent novel factors for potentially increasing TAG accumulation in a variety of oil crops.

In vitro culture and tissue-derived specific expression of melanocytes from ovary of adult Silky Fowl

BackgroundThe presence of a significant number of melanocytes in the ovary and follicular membrane of Silky Fowl suggests their potential involvement in follicle development. Currently, there is a lack of available data regarding to the isolation of primary melanocytes from adult chickens. To date, primary melanocytes and their in vitro culture system have been successfully conducted in the peritoneum of chicken embryos. Herein, melanocytes from silky fowl ovaries were isolated and identified. MethodsSilky Fowl ovaries were obtained by mixed digestion of 0.1% collagenase II and 0.25% trypsin-EDTA. Melanocytes could be further purified and cultured up to five generations in vitro. RNA-seq analysis was used to investigate whether there were differences in the functional status of melanocytes in different tissues and developmental stages. ResultsConsequently, differential gene expressions between peritoneal and ovarian melanocytes were compared. These findings demonstrated that the Silky Fowl ovary had higher expression levels of genes involved in the production of sexual hormones and melanogenesis, while those of melanocytes derived from the peritoneum were involved in amino acid metabolism, lipid synthesis, and overall metabolic rates. This suggests that the role of melanocytes is dependent on the origin tissue and developmental stage, and is tightly connected to the function of the specific source tissue from which the cells were derived. ConclusionsThis study provides a method for isolating adult melanocytes and serve as a basis for further investigate the effect of SFOM on germ cells.

New Insights into the Link Between Melanoma and Obesity.

The significant increase in the incidence of obesity represents a global health crisis. Obesity is actually a multi-organ disease affecting the entire organism; hence, skin is no exception. As the functional alterations in the adipose tissue are contributing factors to many diseases, including cancer, recently, the link between the development of melanoma skin cancer and obesity gains increased attention. Besides several other factors, the increase of adipose stromal/stem cells (ASCs) impacts cancer progression. Moreover, increased production of cytokines and growth factors done by ASCs induces tumorigenesis and metastasis. The chronic inflammatory state that is sustained by this metabolic imbalance favors skin malignancies, melanoma included. Cutaneous melanoma, as an aggressive skin cancer, has both intrinsic and extrinsic risk factors where sun exposure and lifestyles are the main environmental factors inducing this skin cancer. With the advent of recent targeted and immune-based therapies in melanoma, the link between obesity and the efficacy of these therapies in melanoma remains controversial. A recent molecular relationship between the melanocortin pathway appending to both melanin synthesis and obesity was established. The biology of adipokines, molecules secreted by the adipose tissue, is linked to inflammation, and their molecular pathways can be involved in angiogenesis, migration, invasion, and proliferation of melanoma cells. In melanoma cells, among the most noticeable metabolic reprogramming characteristics is an increased rate of lipid synthesis. Lipid mediators impact classical oncogenic pathways, affecting melanoma progression. The chapter will tackle also the practical implications for melanoma prevention and treatment, namely, how metabolic manipulation can be exploited to overcome immunosuppression and support immune checkpoint blockade efficacy.

CYCLIN-DEPENDENT KINASE 8 positively regulates oil synthesis by activating WRINKLED1 transcription.

CYCLIN-DEPENDENT KINASE 8 (CDK8), a component of the kinase module of the Mediator complex in Arabidopsis, is involved in many processes, including flowering, plant defense, drought, and energy stress responses. Here, we investigated cdk8 mutants and CDK8-overexpressing lines to evaluate whether CDK8 also plays a role in regulating lipid synthesis, an energy-demanding anabolism. Quantitative lipid analysis demonstrated significant reductions in lipid synthesis rates and lipid accumulation in developing siliques and seedlings of cdk8, and conversely, elevated lipid contents in wild-type seed overexpressing CDK8. Transactivation assays show that CDK8 is necessary for maximal transactivation of the master seed oil activator WRINKLED1 (WRI1) by the seed maturation transcription factor ABSCISIC ACID INSENSITIVE3, supporting a direct regulatory role of CDK8 in oil synthesis. Thermophoretic studies show GEMINIVIRUS REP INTERACTING KINASE1, an activating kinase of KIN10 (a catalytic subunit of SUCROSE NON-FERMENTING1-RELATED KINASE1), physically interacts with CDK8, resulting in its phosphorylation and degradation in the presence of KIN10. This work defines a mechanism whereby, once activated, KIN10 downregulates WRI1 expression and suppresses lipid synthesis via promoting the degradation of CDK8. The KIN10-CDK8-dependent regulation of lipid synthesis described herein is additional to our previously reported KIN10-dependent phosphorylation and degradation of WRI1.

Metabolic responses in blood-stage malaria parasites associated with increased and decreased sensitivity to PfATP4 inhibitors

BackgroundSpiroindolone and pyrazoleamide antimalarial compounds target Plasmodium falciparum P-type ATPase (PfATP4) and induce disruption of intracellular Na+ homeostasis. Recently, a PfATP4 mutation was discovered that confers resistance to a pyrazoleamide while increasing sensitivity to a spiroindolone. Transcriptomic and metabolic adaptations that underlie this seemingly contradictory response of P. falciparum to sublethal concentrations of each compound were examined to understand the different cellular accommodation to PfATP4 disruptions.MethodsA genetically engineered P. falciparum Dd2 strain (Dd2A211V) carrying an Ala211Val (A211V) mutation in PfATP4 was used to identify metabolic adaptations associated with the mutation that results in decreased sensitivity to PA21A092 (a pyrazoleamide) and increased sensitivity to KAE609 (a spiroindolone). First, sublethal doses of PA21A092 and KAE609 causing substantial reduction (30–70%) in Dd2A211V parasite replication were identified. Then, at this sublethal dose of PA21A092 (or KAE609), metabolomic and transcriptomic data were collected during the first intraerythrocytic developmental cycle. Finally, the time-resolved data were integrated with a whole-genome metabolic network model of P. falciparum to characterize antimalarial-induced physiological adaptations.ResultsSublethal treatment with PA21A092 caused significant (p < 0.001) alterations in the abundances of 91 Plasmodium gene transcripts, whereas only 21 transcripts were significantly altered due to sublethal treatment with KAE609. In the metabolomic data, a substantial alteration (≥ fourfold) in the abundances of carbohydrate metabolites in the presence of either compound was found. The estimated rates of macromolecule syntheses between the two antimalarial-treated conditions were also comparable, except for the rate of lipid synthesis. A closer examination of parasite metabolism in the presence of either compound indicated statistically significant differences in enzymatic activities associated with synthesis of phosphatidylcholine, phosphatidylserine, and phosphatidylinositol.ConclusionThe results of this study suggest that malaria parasites activate protein kinases via phospholipid-dependent signalling in response to the ionic perturbation induced by the Na+ homeostasis disruptor PA21A092. Therefore, targeted disruption of phospholipid signalling in PA21A092-resistant parasites could be a means to block the emergence of resistance to PA21A092.

LC-MS analysis of D2O-labelled soil suggests a large fraction of membrane lipid exists within slow growing microbes

Measuring the growth of microbes is essential for understanding soil function, yet it remains challenging. Knowing the rate of synthesis of polar lipids that comprise microbial membranes would serve as an indicator of microbial growth, and also improve understanding of the biogeochemical cycling of polar lipids. The aim of this study was to develop D2O-labelling of intact polar lipids (D2O-intact lipid-SIP) as a culture- and gene-independent way of probing synthesis of membrane lipids by soil microbes. To test the feasibility of coupling D2O labelling with liquid chromatography-mass spectrometry (LC-MS) quantification, and determine appropriate incubation durations, we incubated two soils with 50 atom% D2O for durations between 3 h and 46 days. We first improved the chromatographic separation to reduce the number of co-eluting lipids and enable easier quantification of D2O enrichment. Increasing column length from 150 mm to 500 mm and the gradient separation from 45 to 300 min increased 3.4-fold the number of resolved peaks, and meant that chromatographically co-eluting lipids were generally separated in the mass dimension by a minimum of ten Da. Quantification of 2H enrichment of a broad spectrum of lipids was possible in soils incubated with 50 atom% D2O for 27 h. Enrichment and rate of lipid synthesis were determined for 34–38 membrane lipids that collectively accounted for >80% of the lipid pool. There was ten-fold variation among individual lipids in rates of synthesis and turnover, which presumably reflects differences in growth rate and abundance of soil taxa. Turnover differed among classes from 1.2 to 1.5 years in phosphatidylcholine, 0.54–0.98 years in diacylglyceryl-N,N,N-trimethylhomoserine, and 0.42–0.72 years in phosphatidylethanolamine. By quantifying the isotopologue distribution, LC-MS revealed the average turnover comprised a large population of lipid that remained unlabelled (93–95% unlabelled after 27 h and 66–75% unlabelled after 46 days), and a small population of lipid that had incorporated varying numbers of 2H. These observations are consistent with much of the microbial lipid pool residing in microbes with negligible growth, and a smaller proportion in microbes with a range of growth rates. Accordingly turnover calculated solely for the active fraction of lipid was a more rapid 20–30 days. The slow average turnover of membrane lipids likely also reflects efficient microbial recycling of lipids reducing the amount of lipid synthesis required to support growth.

Longitudinal spatial mapping of lipid metabolites reveals pre-symptomatic changes in the hippocampi of Huntington's disease transgenic mice

In Huntington's disease (HD), a key pathological feature includes the development of inclusion-bodies of fragments of the mutant huntingtin protein in the neurons of the striatum and hippocampus. To examine the molecular changes associated with inclusion-body formation, we applied MALDI-mass spectrometry imaging and deuterium pulse labelling to determine lipid levels and synthesis rates in the hippocampus of a transgenic mouse model of HD (R6/1 line). The R6/1 HD mice lacked inclusions in the hippocampus at 6 weeks of age (pre-symptomatic), whereas inclusions were pervasive by 16 weeks of age (symptomatic). Hippocampal subfields (CA1, CA3 and DG), which formed the highest density of inclusion formation in the mouse brain showed a reduction in the relative abundance of neuron-enriched lipids that have roles in neurotransmission, synaptic plasticity, neurogenesis, and ER-stress protection. Lipids involved in the adaptive response to ER stress (phosphatidylinositol, phosphatidic acid, and ganglioside classes) displayed increased rates of synthesis in HD mice relative to WT mice at all the ages examined, including prior to the formation of the inclusion bodies. Our findings, therefore, support a role for ER stress occurring pre-symptomatically and potentially contributing to pathological mechanisms underlying HD.

Arduino Soft Sensor for Monitoring Schizochytrium sp. Fermentation, a Proof of Concept for the Industrial Application of Genome-Scale Metabolic Models in the Context of Pharma 4.0

Schizochytrium sp. is a microorganism cultured for producing docosahexaenoic acid (DHA). Genome-scale metabolic modeling (GEM) is a promising technique for describing gen-protein-reactions in cells, but with still limited industrial application due to its complexity and high computation requirements. In this work, we simplified GEM results regarding the relationship between the specific oxygen uptake rate (−rO2), the specific growth rate (µ), and the rate of lipid synthesis (rL) using an evolutionary algorithm for developing a model that can be used by a soft sensor for fermentation monitoring. The soft sensor estimated the concentration of active biomass (X), glutamate (N), lipids (L), and DHA in a Schizochytrium sp. fermentation using the dissolved oxygen tension (DO) and the oxygen mass transfer coefficient (kLa) as online input variables. The soft sensor model described the biomass concentration response of four reported experiments characterized by different kLa values. The average range normalized root-mean-square error for X, N, L, and DHA were equal to 1.1, 1.3, 1.1, and 3.2%, respectively, suggesting an acceptable generalization capacity. The feasibility of implementing the soft sensor over a low-cost electronic board was successfully tested using an Arduino UNO, showing a novel path for applying GEM-based soft sensors in the context of Pharma 4.0.

A review on unit operations, challenges, opportunities, and strategies to improve algal based biodiesel and biorefinery

Globally, the demand for energy is increasing with an emphasis on green fuels for a sustainable future. As the urge for alternative fuels is accelerating, microalgae have emerged as a promising source that can not only produce high lipid but many other platform chemicals. Moreover, it is a better alternative in comparison to conventional feedstock due to yearlong easy and mass cultivation, carbon fixation, and value-added products extraction. To date, numerous studies have been done to elucidate these organisms for large-scale fuel production. However, enhancing the lipid synthesis rate and reducing the production cost still remain a major bottleneck for its economic viability. Therefore, this study compiles information on algae-based biodiesel production with an emphasis on its unit operations from strain selection to biofuel production. Additionally, strategies to enhance lipid accumulation by incorporating genetic, and metabolic engineering and the use of leftover biomass for harnessing bio-products have been discussed. Besides, implementing a biorefinery for extracting oil followed by utilizing leftover biomass to generate value-added products such as nanoparticles, biofertilizers, biochar, and biopharmaceuticals has also been discussed.

An evaluation of blood glucose and lipid profile in female hypothyroidism patients in Kerbala province, Iraq

Introduction and Aim: Hypothyroidism is a common metabolic disorder caused by inadequate secretion of the thyroid hormone by the thyroid glands. The condition impacts various metabolic processes including glucose synthesis, lipid synthesis, mobilization and metabolic rate. This study aimed to evaluate the physiological factors associated with female hypothyroidism patients of Kerbala province of Iraq. Materials and Methods: Fifty females (35 with hypothyroidism and 15 normal) aged between 20-49 years were included in the study. Blood sample was collected from each individual and subjected to thyroid function test (TFT), lipid profile test (LPT) and fasting blood glucose (FBG). Results: The study showed a significant (P?0.001) increase in thyroid stimulating hormone (TSH) levels as compared to control. While a significant decrease was seen in thyroxin (T4) levels in comparison to controls, no significant difference was seen for triiodothyronine (T3) levels in both groups. Low?density lipoprotein (LDL), Triglycerides (TG), total cholesterol (TC) was significantly increased (P?0.001) while high density lipoprotein (HDL) was observed to significantly decrease as compared to control group. High significant elevation (P?0.001) in fasting blood glucose (FBG) was seen in patients with hypothyroidism as compared to control. Conclusion: The results obtained in this study show that hypothyroidism in females to be significantly associated with increase in dyslipidemia and blood glucose levels.

Serine active site containing protein 1 depletion alters lipid metabolism and protects against high fat diet-induced obesity in mice

ObjectiveAlthough the serine active site containing 1 (SERAC1) protein is essential for cardiolipin remodeling and cholesterol transfer, its physiological role in whole-body energy metabolism remains unclear. Thus, we investigated the role of SERAC1 in lipid distribution and metabolism in mice. MethodsCRISPR/Cas9 was used to create homozygous Serac1 knockout mice. A range of methods, including electron microscopy, histological analysis, DNA sequencing, glucose and insulin tolerance tests, and biochemical analysis of serum lipid levels, were used to assess lipid distribution and rates of lipid synthesis in mice. ResultsWe found that Serac1 depletion in mice prevented high-fat diet-induced obesity but did not affect energy expenditure. The liver was affected by Serac1 depletion, but adipose tissues were not. Serac1 depletion was shown to impair cholesterol transfer from the liver to the serum and led to an imbalance in cholesterol distribution. The livers from mice with Serac1 depletion showed increased cholesterol synthesis because the levels of cholesterol synthesis enzymes were upregulated. Moreover, the accumulation of hepatic lipid droplets in mice with Serac1 depletion were decreased, suggesting that SERAC1 depletion may decrease the risk for hepatic steatosis in high fat diet-induced mice. ConclusionOur findings demonstrate that SERAC1 can serve as a potential target for the treatment or prevention of diet-induced hepatic lipid metabolic disorders.

Unrestricted availability of α-ketoglutarate influences biomass production in the cyanobacterium Nostoc muscorum Meg 1 by impacting rates of photosynthesis, nitrogen fixation and lipid synthesis

Unrestricted availability of α-ketoglutarate influences biomass production in the cyanobacterium Nostoc muscorum Meg 1 by impacting rates of photosynthesis, nitrogen fixation and lipid synthesis

A kinetic model of heterotrophic and mixotrophic cultivation of the potential biofuel organism microalgae Chlorella sorokiniana

Better microalgal growth performance under heterotrophic and mixotrophic conditions can advance production of environmentally sustainable, lipid-based third-generation biofuels. In this study, an unstructured kinetic growth model was developed by extending a Haldane-based model to account and predict the enhancing and/or inhibitory effects of substrate (i.e. initial glucose concentration, nitrogen concentration, and light intensity) on the growth and lipid accumulation rates of the microalgae Chlorella sorokiniana during its heterotrophic and mixotrophic cultivation. The model considered a nitrogen-deprived phase of cultivation during which lipid synthesis and accumulation rates increase. Model-derived estimations for glucose and nitrogen consumption, cell growth, and lipid production under heterotrophic and mixotrophic conditions, respectively, were validated and in good agreement with experimental measurements, with R2 correlation values ranging from 0.83 to 0.99. Sensitivity analysis showed that the reaction rate constant of nitrogen consumption (KNX) has a “significant effect” on both lipid production and nitrogen consumption, suggesting that rapid depletion of nitrogen is favorable to increase lipid content instead of cell growth. The rate of cell growth declined on the 4th day during heterotrophic cultivation but remained constant after the 4th day during mixotrophic cultivation under initial glucose concentrations of 2.29, 4.32, and 6.19 g L−1. Our model further confirmed experimental observations that the best growth performance and highest lipid production are obtained under mixotrophic conditions compared to heterotrophic conditions.

Optimization of Lipid Production by Schizochytrium limacinum Biomass Modified with Ethyl Methane Sulfonate and Grown on Waste Glycerol.

One of the most promising avenues of biofuel research relates to using waste as a starting feedstock to produce liquid or gaseous energy carriers. The global production of waste glycerol by the refinery industry is rising year after year. The aim of the present study was to examine the effect of ethyl methane sulfonate (EMS) on the growth rates and intracellular lipid accumulation in heterotrophically-cultured Schizochytrium limacinum microalgae, grown on waste glycerol as the carbon source. The strain S. limacinum E20, produced by incubating a reference strain in EMS for 20 min, was found to perform the best in terms of producing biomass (0.054 gDW/dm3·h) and accumulating intracellular bio-oil (0.021 g/dm3·h). The selected parameters proved to be optimal for S. limacinum E20 biomass growth at the following values: temperature 27.3 °C, glycerol level 249.0 g/dm3, oxygen in the culture 26%, and yeast extract concentration 45.0 g/dm3. In turn, the optimal values for lipid production in an S. limacinum E20 culture were: temperature 24.2 °C, glycerol level 223.0 g/dm3, oxygen in the culture 10%, and yeast extract concentration 10.0 g/dm3. As the process conditions are different for biomass growth and for intracellular lipid accumulation, it is recommended to use a two-step culture process, which resulted in a lipid synthesis rate of 0.41 g/dm3·h.

Kinetic complexities of triacylglycerol accumulation in developing embryos from Camelina sativa provide evidence for multiple biosynthetic systems

Quantitative flux maps describing glycerolipid synthesis can be important tools for rational engineering of lipid content and composition in oilseeds. Lipid accumulation in cultured embryos of Camelina sativa is known to mimic that of seeds in terms of rate of lipid synthesis and composition. To assess the kinetic complexity of the glycerolipid flux network, cultured embryos were incubated with [14C/13C]glycerol, and initial and steady state rates of [14C/13Cglyceryl] lipid accumulation were measured. At steady state, the linear accumulations of labeled lipid classes matched those expected from mass compositions. The system showed an apparently simple kinetic precursor–product relationship between the intermediate pool, dominated by diacylglycerol (DAG) and phosphatidylcholine (PC), and the triacylglycerol (TAG) product. We also conducted isotopomer analyses on hydrogenated lipid class species. [13C3glyceryl] labeling of DAG and PC, together with estimates of endogenous [12C3glyceryl] dilution, showed that each biosynthetically active lipid pool is ∼30% of the total by moles. This validates the concept that lipid sub-pools can describe lipid biosynthetic networks. By tracking the kinetics of [13C3glyceryl] and [13C2acyl] labeling, we observed two distinct TAG synthesis components. The major TAG synthesis flux (∼75%) was associated with >95% of the DAG/PC intermediate pool, with little glycerol being metabolized to fatty acids, and with little dilution from endogenous glycerol; a smaller flux exhibited converse characteristics. This kinetic heterogeneity was further explored using postlabeling embryo dissection and differential lipid extractions. The minor flux was tentatively localized to surface cells across the whole embryo. Such heterogeneity must be recognized in order to construct accurate gene expression patterns and metabolic networks describing lipid biosynthesis in developing embryos.

Fine-Tuning Lipid Metabolism by Targeting Mitochondria-Associated Acetyl-CoA-Carboxylase 2 in BRAFV600E Papillary Thyroid Carcinoma.

Background: BRAFV600E acts as an ATP-dependent cytosolic kinase. BRAFV600E inhibitors are widely available, but resistance to them is widely reported in the clinic. Lipid metabolism (fatty acids) is fundamental for energy and to control cell stress. Whether and how BRAFV600E impacts lipid metabolism regulation in papillary thyroid carcinoma (PTC) is still unknown. Acetyl-CoA carboxylase (ACC) is a rate-limiting enzyme for de novo lipid synthesis and inhibition of fatty acid oxidation (FAO). ACC1 and ACC2 genes encode distinct isoforms of ACC. The aim of our study was to determine the relationship between BRAFV600E and ACC in PTC. Methods: We performed RNA-seq and DNA copy number analyses in PTC and normal thyroid (NT) in The Cancer Genome Atlas samples. Validations were performed by using assays on PTC-derived cell lines of differing BRAF status and a xenograft mouse model derived from a heterozygous BRAFWT/V600E PTC-derived cell line with knockdown (sh) of ACC1 or ACC2. Results:ACC2 mRNA expression was significantly downregulated in BRAFV600E-PTC vs. BRAFWT-PTC or NT clinical samples. ACC2 protein levels were downregulated in BRAFV600E-PTC cell lines vs. the BRAFWT/WT PTC cell line. Vemurafenib increased ACC2 (and to a lesser extent ACC1) mRNA levels in PTC-derived cell lines in a BRAFV600E allelic dose-dependent manner. BRAFV600E inhibition increased de novo lipid synthesis rates, and decreased FAO due to oxygen consumption rate (OCR), and extracellular acidification rate (ECAR), after addition of palmitate. Only shACC2 significantly increased OCR rates due to FAO, while it decreased ECAR in BRAFV600E PTC-derived cells vs. controls. BRAFV600E inhibition synergized with shACC2 to increase intracellular reactive oxygen species production, leading to increased cell proliferation and, ultimately, vemurafenib resistance. Mice implanted with a BRAFWT/V600E PTC-derived cell line with shACC2 showed significantly increased tumor growth after vemurafenib treatment, while vehicle-treated controls, or shGFP control cells treated with vemurafenib showed stable tumor growth. Conclusions: These findings suggest a potential link between BRAFV600E and lipid metabolism regulation in PTC. BRAFV600E downregulates ACC2 levels, which deregulates de novo lipid synthesis, FAO due to OCR, and ECAR rates. ShACC2 may contribute to vemurafenib resistance and increased tumor growth. ACC2 rescue may represent a novel molecular strategy for overcoming resistance to BRAFV600E inhibitors in refractory PTC.

Lipid metabolic Reprogramming: Role in Melanoma Progression and Therapeutic Perspectives.

Simple SummaryMelanoma is a devastating skin cancer characterized by an impressive metabolic plasticity. Melanoma cells are able to adapt to the tumor microenvironment by using a variety of fuels that contribute to tumor growth and progression. In this review, the authors summarize the contribution of the lipid metabolic network in melanoma plasticity and aggressiveness, with a particular attention to specific lipid classes such as glycerophospholipids, sphingolipids, sterols and eicosanoids. They also highlight the role of adipose tissue in tumor progression as well as the potential antitumor role of drugs targeting critical steps of lipid metabolic pathways in the context of melanoma.Metabolic reprogramming contributes to the pathogenesis and heterogeneity of melanoma. It is driven both by oncogenic events and the constraints imposed by a nutrient- and oxygen-scarce microenvironment. Among the most prominent metabolic reprogramming features is an increased rate of lipid synthesis. Lipids serve as a source of energy and form the structural foundation of all membranes, but have also emerged as mediators that not only impact classical oncogenic signaling pathways, but also contribute to melanoma progression. Various alterations in fatty acid metabolism have been reported and can contribute to melanoma cell aggressiveness. Elevated expression of the key lipogenic fatty acid synthase is associated with tumor cell invasion and poor prognosis. Fatty acid uptake from the surrounding microenvironment, fatty acid β-oxidation and storage also appear to play an essential role in tumor cell migration. The aim of this review is (i) to focus on the major alterations affecting lipid storage organelles and lipid metabolism. A particular attention has been paid to glycerophospholipids, sphingolipids, sterols and eicosanoids, (ii) to discuss how these metabolic dysregulations contribute to the phenotype plasticity of melanoma cells and/or melanoma aggressiveness, and (iii) to highlight therapeutic approaches targeting lipid metabolism that could be applicable for melanoma treatment.

Regulation of hepatic genes related to lipid metabolism and antioxidant enzymes by sodium butyrate supplementation

BackgroundRapid influx of energy caused by fasting/refeeding repeatedly enhances fatty acid synthesis leading to triacylglycerol accumulation and production of reactive oxygen species (ROS), increasing the risk of non-alcoholic steatohepatitis (NASH). Previous studies have reported that the ingestion of butyrate is effective at preventing hepatic disorders, which are accompanied by fat accumulation and inflammation. The aim of this study is to reveal the mechanism of action of butyrate, and thus we investigated the effects of dietary butyrate on the expressions of antioxidant enzymes in the livers of rats during refeeding following fasting. MethodsThirty-seven male rats were divided into six groups (6–7 animals per group): non-fasting, fasting, refeeding with a high sucrose diet as control for 12 or 24 h, and refeeding with a high sucrose diet containing 5% sodium butyrate (NaB) for 12 or 24 h. All groups except the non-fasting group were fasted for 72 h before refeeding. Statistical analysis was conducted among 4 refeeding groups (refeeding with the control diet for 12 or 24 h, and refeeding with a diet containing NaB for 12 or 24 h). ResultsSupplementation with NaB significantly reduced (p < 0.05) fatty acid synthase (Fas) gene expression and increased the expression of the carnitine palmitoyltransferase 1α (Cpt1a) gene, resulting in reduced triacylglycerol content in the livers of rats refed the NaB diet compared with controls at 24 h after the start of refeeding. The mRNA levels of the genes related to glutathione synthesis were significantly higher (p < 0.05) in the livers of the butyrate group than the control group. In addition, the mRNA level of Foxo3a, a transcription factor that regulates the expressions of antioxidant enzymes, was higher in the butyrate group than controls. The acetylation levels of histone H4 around the Foxo3a gene tended to be increased (p = 0.055) by refeeding with the NaB diet. ConclusionNaB supplementation in the diet for refeeding reduced the rate of lipid synthesis and stimulated fatty acid oxidation in the liver, which inhibited fat accumulation and the risk of NASH. The transcriptional regulation of Foxo3a involves histone acetylation around the gene.

Effects of Potassium Fertilization on Oil Palm Fruit Metabolism and Mesocarp Lipid Accumulation.

Potassium fertilization is commonly practiced in oil palm (Elaeis guineensis) plantations to increase yield. However, its effects on fruit oil content and composition are not well documented. Here, we conducted bunch, metabolomics, and oil composition analyses in two contrasting crosses (Deli × La Mé and Deli × Yangambi) grown under different K fertilization conditions. K availability impacted bunch oil content, resulting in lower water content and higher oil proportion in fruit mesocarp, in Deli × La Mé only, thus showing differential responses of crosses to K. Oil composition at maturity did not significantly change under low K conditions despite clear alterations in fruit metabolism associated with lipid production during maturation, demonstrating the resilience of oil biosynthetic metabolism. However, the analysis of variance in oil content (across K treatments and crosses) demonstrates that sugar availability, lipid synthesis rates, and metabolic recycling are all important in determining the oil content.