Form Of Triglycerides Research Articles

Superior bioavailability of EPA and DHA from a L-lysine salt formulation: a randomized, three-way crossover study.

Omega-3 fatty acids, including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are polyunsaturated fatty acids (PUFAs) with notable health benefits. Due to limited physiological production and insufficient dietary supply, external supplementation is important. This study aimed to compare the pharmacokinetics and bioavailability of EPA and DHA in AvailOm® omega-3-lysine salt (Lys-FFA) versus standard ethyl ester (EE) and triglyceride (TG) formulations after a single oral dose in healthy subjects. A randomized, three-way crossover study was conducted with 21 healthy subjects. Twenty-one subjects (10 men, 11 women) completed the study. The average age was 41.7 years, and the mean body mass index was 23.0 kg/m2. The Lys-FFA formulation showed significantly higher uptake of omega-3 fatty acids (EPA+DHA combined and each individually) compared to EE. Specifically, Lys-FFA had a 9.33-fold (0-12 h) and 8.09-fold (0-24 h) higher bioavailability of EPA+DHA than EE and a 1.57-fold (0-12 h) and 1.44-fold (0-24 h) higher bioavailability than TG. ΔCmax and Tmax also favored Lys-FFA over EE. Under fasting conditions, the absorption of EPA and DHA from EE is limited due to the need for enzymatic cleavage before absorption. This requirement is bypassed with Lys-FFA, which does not need cleavage. The study demonstrates that EPA and DHA lysine salt (Lys-FFA) offers superior bioavailability compared to EE and triglyceride forms, presenting a more effective supplementation option.German Clinical Trials Register, DRKS-ID: DRKS00029183.

Docosahexaenoic Acid (DHA) Supplementation in a Triglyceride Form Prevents from Polyglutamine-Induced Dysfunctions in Caenorhabditis elegans.

A common hallmark of neurodegenerative diseases is the accumulation of polypeptide aggregates in neurons. Despite the primary cause of these diseases being inherently genetic, their development can be delayed with proper preventive treatments. Long-chain polyunsaturated fatty acids (ω-3 LCPUFA) are promising bioactive nutrients that are beneficial for brain health. In this study, the impact of an oil rich in a structured form of docosahexaenoic acid (DHA) triglyceride (TG) was assessed in a Caenorhabditis elegans model expressing long poly-glutamine (polyQ) chains, which mimics the symptomatology of polyQ-related neurodegenerative diseases such as Huntington's disease (HD), among others. The lifespan, the motility, the number of polyQ aggregates, the oxidative stress resistance, and the cognitive performance associated with sensitive stimuli was measured in mutant nematodes with polyQ aggregates. Overall, DHA-TG at 0.5 µM improved the lifespan, the motility, the oxidative stress resistance, and the cognitive performance of the nematodes, emphasizing the protection against serotonergic synapse dysfunction. Furthermore, the treatment reduced the polyQ aggregates in the nematodes. The data described herein shed light on the connection between DHA and the cognitive performance in neurodegenerative diseases and demonstrated the potential of DHA-TG as nutritional co-adjuvant to prevent the development of polyQ-associated dysfunctions.

Bta-miR-224 regulates milk fat metabolism by targeting FABP4 in bovine mammary epithelial cells

Milk fat is produced and secreted by the mammary gland, which is mainly regulated by diet and gene-molecule network. Therefore, understanding the molecular mechanism of milk fat synthesis is of practical significance for improving milk quality. Fatty acid-binding protein 4 (FABP4) is a candidate messenger RNA (mRNA) closely linked to milk fat metabolism obtained from transcriptomic analysis of mammary epithelial cells of cows in the pre-existing high- and low-milk-fat groups, and its expression pattern and function are still unclear. The qRT-PCR results depicted that FABP4 was highly expressed in bovine mammary epithelial cells (BMECs) in breast tissues and the high milk fat group. Subsequently, the regulatory effects of FABP4 on BMECs were analyzed by CCK8, EdU, and flow cytometry, and the results demonstrated that FABP4 inhibited the proliferation and viability of BMECs and promoted their apoptosis. Next, the effect of FABP4 on milk lipid metabolism was explored. pEGFP-N1-FABP4 was transfected into BMECs, and FABP4 upregulated the expression levels of the milk lipid marker genes XDH, PPARG, and ACSS2, and promoted the formation of triglycerides (TGs), cholesterol, lipid droplets, and β-casein. Strong interactions between FABP4 and PPARG were identified using STRING prediction. Western blotting revealed that FABP4 interacted with PPARG to promote PPARG expression, while the opposite result was observed after interfering with FABP4. The gene regulation of microRNA (miRNA) is essential for fatty acid metabolism and synthesis. Predicted by website and combined with pre-miRNA transcriptome sequencing results, we hypothesized that FABP4 might be the target gene of bta-miR-224. The results of the dual-luciferase reporter gene and qRT-PCR revealed that bta-miR-224 negatively regulated FABP4 expression by targeting the 3′-UTR of FABP4. By exploring the function of bta-miR-224, we observed that bta-miR-224 mimics downregulated the expression of the milk fat marker genes AGPAT6, ACSS2, and XDH and inhibited TG synthesis and lipid droplet secretion. However, the bta-miR-224 inhibitor depicted the opposite results. In conclusion, FABP4 plays a crucial role in regulating BMEC proliferation and differentiation. Bta-miR-224 targeting FABP4 may promote biological processes such as TG synthesis and lipid droplet formation through PPARG, which lays a solid foundation for further analysis of the functional mechanism of milk lipid metabolism in dairy cows from a miRNA-mRNA perspective.

Subacute Effects of Moderate-Intensity Aerobic Exercise in the Fasted State on Cell Metabolism and Signaling in Sedentary Rats.

Background: Physical inactivity induces insulin resistance (IR) and metabolic imbalances before any significant changes in adiposity. Recent studies suggest that the beneficial effects of exercise can be potentiated if performed while fasting. This work aimed to compare the subacute effects of fed- and fasted-state single-bout exercise on biochemical parameters and cellular signaling in the metabolism. Methods: The animals were allocated into fed rest (FER), fasting rest (FAR), fed exercise (FEE), and fasting exercise (FAE) groups. The exercise protocol was a 30 min treadmill session at 60% of V˙O2max. The fasting groups fasted for 8 h before exercise and were killed after 12 h post-exercise. Results: Soleus glycogen concentration increased only in the fasting groups, whereas the triglyceride (TGL) content increased in brown adipose tissue (BAT) and liver in the FAE. The FAE showed decreased plasma total cholesterol concentration compared withthe FAR group. Immunocontent of HSP70, SIRT1, UCP-1, and PGC1-α did not change in any tissue investigated. Conclusions: Our results indicate that physical exercise while fasting can have beneficial metabolic effects on sedentary animals. Remarkably, in the FAE group, there was a reduction in total plasma cholesterol and an increase in the capacity of BAT to metabolize and store nutrients in the form of TGLs.

Production of docosahexaenoic acid through enzymatic hydrolysis of Omega-3 rich oil

Docosahexaenoic acid (DHA), an essential omega-3 fatty acid, is crucial for the normal development and function of the brain. Its production can be achieved through the partial hydrolysis of DHA-rich triglycerides catalyzed by lipases, particularly from fish oils. In this work, the characterization of anchovy oil capsules revealed that they offer a pure and concentrated source of DHA, with more than 90 % of the oil in the form of triglycerides. Therefore, the hydrolysis reaction was studied with the aim of releasing 100 % of the DHA present in this oil, using different immobilized lipases with maximum enzyme loading on the hydrophobic support Immobeads-C18. The study’s results revealed that our immobilization strategy through hydrophobic adsorption improved the catalytic properties of activity and selectivity of the TLL lipase compared to other biocatalysts described in the literature. Additionally, complete hydrolysis of the oil was achieved in just 24 h with the NS40-C18 derivative, which could be reused up to 6 cycles without loss of activity.

Effects of Supplementation with Essential Fatty Acids and Conjugated Linoleic Acids on Muscle Structure and Fat Deposition in Lactating Holstein Cows

High-yielding dairy cows need diets that meet their energy demand and contain sufficient essential nutrients such as n-3 fatty acids (FAs). Conjugated linoleic acid (CLA) is able to relieve the energy metabolism, but common corn silage and concentrate-based diets contain insufficient amounts of essential fatty acids (EFA). Abomasal infusion was used in the current study to supplement cows from 9 weeks antepartum to 9 weeks postpartum with either coconut oil (CTRL, n = 8), EFA (n = 9), or conjugated linoleic acid (CLA, n = 9), or a combination of both (EFA + CLA, n = 10). The study focused on the effects of FAs on peripheral tissues, such as longissimus muscle (MLD) and adipose tissues, which were harvested after slaughter. Fatty acid composition, muscle fiber and fat cell morphology, muscle fiber type transition, and gene expression were analyzed. Supplemented FAs and their metabolites were increased (p < 0.05) in MLD and intermuscular fat (INTF) but not in subcutaneous fat (SCF). The intramuscular fat content and gene expression of ACACA and FASN were increased in CLA-supplemented cows (p < 0.05). Supplementation did not affect the muscle fiber size and fiber type composition. Supplemented CLA had more effects than EFA, improving the energy balance of cows accompanied with increased triglyceride formation and storage.

Moderate-temperature curing of epoxidized soybean oil for highly efficient coated fertilizer

The use of bio-oil-based polymers in fertilizer coatings has drawn significant academic interest. However, the challenge remains to eliminate toxic chemicals while enhancing comprehensive properties. This study focused on synthesizing a degradable polymer from epoxidized soybean oil (ESO) without organic solvent at low temperature (120°C), accomplished through a modified curing agent (MCA). This MCA was made of an acidic eutectic mixture of phthalic anhydride (PA) and its glycerides, produced from inexpensive, low-toxic phthalic anhydride and glycerol. The process utilized a small quantity of zinc acetate (0.5 wt%) to facilitate the formation of phthalic triglyceride in the MCA and mitigate PA sublimation, resulting in the enhanced cross-link degree, superior mechanical properties and hydrophobicity of the ESO-based resin (ESOR). Under optimal preparation conditions, the solvent-free ESOR-coated fertilizer exhibited an extended longevity of 53 days, with an 80 % phosphorus release. This coating material can undergo hydrolytic degradation in soil and in-situ conversion into carboxylates. These findings hold significant potential for advancing the applications of ESOR in green and sustainable agriculture.

The integral role of de novo lipogenesis in the preparation for seasonal dormancy

Animals can alter their body compositions in anticipation of dormancy to endure seasons with limited food availability. Accumulation of lipid reserves, mostly in the form of triglycerides (TAGs), is observed during the preparation for dormancy in diverse animals, including insects (diapause) and mammals (hibernation). However, the mechanisms involved in the regulation of lipid accumulation and the ecological consequences of failure to accumulate adequate lipid stores in preparation for animal dormancy remain understudied. In the broadest sense, lipid reserves can be accumulated in two ways: the animal either receives lipids directly from the environment or converts the sugars and amino acids present in food to fatty acids through de novo lipogenesis and then to TAGs. Here, we show that preparation for diapause in the Colorado potato beetle (Leptinotarsa decemlineata) involves orchestrated upregulation of genes involved in lipid metabolism with a transcript peak in 8- and 10-d-old diapause-destined insects. Regulation at the transcript abundance level was associated with the accumulation of substantial fat stores. Furthermore, the knockdown of de novo lipogenesis enzymes (ACCase and FAS-1) prolonged the preparatory phase, while the knockdown of fatty acid transportation genes shortened the preparatory phase. Our findings suggest a model in which the insects dynamically decide when to transition from the preparation phase into diapause, depending on the progress in lipid accumulation through de novo lipogenesis.

Impaired GK-GKRP interaction rather than direct GK activation worsens lipid profiles and contributes to long-term complications: a Mendelian randomization study

BackgroundGlucokinase (GK) plays a key role in glucose metabolism. In the liver, GK is regulated by GK regulatory protein (GKRP) with nuclear sequestration at low plasma glucose level. Some GK activators (GKAs) disrupt GK-GKRP interaction which increases hepatic cytoplasmic GK level. Excess hepatic GK activity may exceed the capacity of glycogen synthesis with excess triglyceride formation. It remains uncertain whether hypertriglyceridemia associated with some GKAs in previous clinical trials was due to direct GK activation or impaired GK-GKRP interaction.MethodsUsing publicly available genome-wide association study summary statistics, we selected independent genetic variants of GCKR and GCK associated with fasting plasma glucose (FPG) as instrumental variables, to mimic the effects of impaired GK-GKRP interaction and direct GK activation, respectively. We applied two-sample Mendelian Randomization (MR) framework to assess their causal associations with lipid-related traits, risks of metabolic dysfunction-associated steatotic liver disease (MASLD) and cardiovascular diseases. We verified these findings in one-sample MR analysis using individual-level statistics from the Hong Kong Diabetes Register (HKDR).ResultsGenetically-proxied impaired GK-GKRP interaction increased plasma triglycerides, low-density lipoprotein cholesterol and apolipoprotein B levels with increased odds ratio (OR) of 14.6 (95% CI 4.57–46.4) per 1 mmol/L lower FPG for MASLD and OR of 2.92 (95% CI 1.78–4.81) for coronary artery disease (CAD). Genetically-proxied GK activation was associated with decreased risk of CAD (OR 0.69, 95% CI 0.54–0.88) and not with dyslipidemia. One-sample MR validation in HKDR showed consistent results.ConclusionsImpaired GK-GKRP interaction, rather than direct GK activation, may worsen lipid profiles and increase risks of MASLD and CAD. Development of future GKAs should avoid interfering with GK-GKRP interaction.

Effects of triglyceride and ethyl ester forms of EPA on hepatic lipid metabolism in mice with non-alcoholic fatty liver disease

In this study, the beneficial effects of EPA in ethyl esters (EE) and triacylglycerides (TAG) forms on high fat diet (HFD)-induced non-alcoholic fatty liver disease (NAFLD) were studied and compared. Results indicated that both EPA-TAG and EPA-EE can alleviate pathological features of NAFLD, such as hepatic lipid accumulation and lobular inflammation, with a more pronounced protective effects observed in EPA-TAG treated mice. The integrated hepatic transcriptomic, metabolic and gut microbiota profiles suggest that EPA-TAG and EPA-EE improved hepatic steatosis by suppression of food intake and lipogenesis, promotion of lipid and phospholipid PUFA remodeling, ketogenesis and fatty acids oxidation, possibly via activating the AMPK/adipocytokine signaling pathway. The protective effect of EPA was also associated with the regulation of intestinal flora structure. In general, EPA-TAG was found to be more effective than EPA-EE in preventing HFD-induced NAFLD by reducing appetite, improving hepatic lipid metabolism, increasing energy expenditure, and enhancing gut-liver cross-talk.

Discrimination between the Triglyceride Form and the Ethyl Ester Form of Fish Oil Using Chromatography-Mass Spectrometry.

Although the triglyceride form is the natural form of fish oil found in fish, the ethyl ester form of fish oil, which is used during processing to save costs, is also present on the market. In this study, fatty acids and lipids were determined using gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-linear ion trap mass spectrometry (LC-LIT/MS), respectively, according to developed methods. The identification of fatty acids was based on the mass spectral characteristics and equivalent chain lengths. However, the fatty acid contents of both forms of fish oils are quite similar. The application of the LC-LIT/MS method for the structural characterization of triacylglycerols (TAGs) and the mechanism of LIT/MS fragmentation are also discussed. Neutral losses of CH2=CH2 (m/z 28) and CH3CH2OH (m/z 46), which are LIT/MS characteristics of ethyl ester from fish oil, were found for the first time. The triglyceride form of fish oils was easily and accurately identified using fingerprint chromatography. In conclusion, lipid analysis combined with LC-LIT/MS showed an improved capability to distinguish between types of fish oil.

In Vivo Absorption and Lymphatic Bioavailability of Docosahexaenoic Acid from Microalgal Oil According to Its Physical and Chemical Form of Vectorization.

Docosahexaenoic acid (DHA) is an essential fatty acid (FA) with proven pro-health effects, but improving its bioavailability is becoming a public health issue. The bioavailability of DHA from microalgal (A) oil has been comprehensively assessed, particularly in terms of the molecular structuring capabilities offered by A-oil. Here, we explored the impact of five DHA-rich formulas differing in terms of (i) molecular structure, i.e., ethyl ester (EE), monoglyceride (MG), or triglyceride (TG), and (ii) supramolecular form, i.e., emulsified TG or TG + phospholipids (PL blend) on the lymphatic kinetics of DHA absorption and the lipid characteristics of the resulting lipoproteins. We demonstrated in rats that the conventional A-DHA TG structure afforded more effective DHA absorption than the EE structure (+23%). Furthermore, the A-DHA MG and A-DHA emulsions were the better DHA vectors (AUC: 89% and +42%, respectively) due to improved lipolysis. The A-DHA MG and A-DHA emulsion presented the richest DHA content in TG (+40%) and PL (+50%) of lymphatic chylomicrons, which could affect the metabolic fate of DHA. We concluded that structuring A-DHA in TG or EE form would better serve for tissue and hepatic metabolism whereas A-DHA in MG and emulsion form could better target nerve tissues.

The Effectiveness of Low-Carb Diet vs Low-Fat Diet on Body Composition in People with Obesity: A Literature Review

Background: Obesity is still become a serious problem today. Obesity is caused by excessive adipose tissue. One of many factors that contribute to a person's obesity is food intake. Excess carbohydrate and fat intake will be stored in the form of triglycerides in adipose tissue. In the meantime, Low-Carb Diet (LCD) and Low-Fat Diet (LFD) are one of the most popular treatments on obesity. However there are many pros and cons related to each diet based on several studies. Objectives: The indicated study aims to determine the effectiveness of LCD and LFD on body composition in people with obesity. Methods: The study was conducted through journal and literature review, based on five journal publications, filtered by related keywords. In accordance to inclusion and exclusion criteria within the last ten years in Pubmed/Medline database, Science Direct, and Wiley Online Library with the keywords "Low-Carb Diet", "Low-Fat Diet", "Body Mass Index", "Lipid Levels", "Adipose Tissue", "Obese", and "Body Water". Discussion: Total body mass and fat mass decreased significantly after being given LCD intervention compared to LFD. The group that was given two dietary interventions also losing weight, but there was no changes in body water. In addition, negative effects were found from the LCD and LFD interventions such as constipation, fatigue, polyuria, nausea, vomiting, changes in appetite, and headaches. Kidney failure, ketosis, and premature coronary artery also occurred in the group that was given with LCD intervention. Conclusions: LCD and LFD interventions can affect body composition of people with obesity.

Anti-Obesity Effect of Different Opuntia stricta var. dillenii's Prickly Pear Tissues and Industrial By-Product Extracts in 3T3-L1 Mature Adipocytes.

Opuntia stricta var. dillenii fruit is a source of phytochemicals, such as betalains and phenolic compounds, which may play essential roles in health promotion. The aim of this research was to study the triglyceride-lowering effect of green extracts, obtained from Opuntia stricta var. dillenii fruit (whole fruit, pulp, peel, and industrial by-products (bagasse)) in 3T3-L1 mature adipocytes. The cells were treated on day 12, for 24 h, after the induction of differentiation with the extracts, at doses of 10, 25, 50, or 100 μg/mL. The expression of genes (PCR-RT) and proteins (Western blot) involved in fatty acid synthesis, fatty acid uptake, triglyceride assembly, and triglyceride mobilisation was determined. The fruit pulp extraction yielded the highest levels of betalains, whereas the peel displayed the greatest concentration of phenolic compounds. The extracts from whole fruit, peel and pulp were effective in reducing triglyceride accumulation at doses of 50 μg/mL or higher. Bagasse did not show this effect. The main mechanisms of action underpinning this outcome encompass a reduction in fatty acids synthesis (de novo lipogenesis), thus limiting their availability for triglyceride formation, alongside an increase in triglyceride mobilisation. However, their reliance is contingent upon the specific Opuntia extract.

Engineering Yarrowia lipolytica for Sustainable Production of the Pomegranate Seed Oil-Derived Punicic Acid.

Punicic acid is a conjugated linolenic acid with various biological activities including antiobesity, antioxidant, anticancer, and anti-inflammatory effects. It is often used as a nutraceutical, dietary additive, and animal feed. Currently, punicic acid is primarily extracted from pomegranate seed oil, but it is restricted due to the extended growth cycle, climatic limitations, and low recovery level. There have also been reports on the chemical synthesis of punicic acid, but it resulted in a mixture of structurally similar isomers, requiring additional purification/separation steps. In this study, a comprehensive strategy for the production of punicic acid in Yarrowia lipolytica was implemented by pushing the supply of linoleic acid precursors in a high-oleic oil strain, expressing multiple copies of the fatty acid conjugase gene from Punica granatum, engineering the acyl-editing pathway to improve the phosphatidylcholine pool, and promoting the assembly of punicic acid in the form of triglycerides. The optimal strain with high oil production capacity and a significantly increased punicic acid ratio accumulated 3072.72 mg/L punicic acid, accounting for 6.19% of total fatty acids in fed-batch fermentation, providing a viable, sustainable, and green approach for punicic acid production to substitute plant extraction and chemical synthesis production.

Lipogenic stearoyl-CoA desaturase-1 (SCD1) targeted virtual screening for chemical inhibitors: molecular docking / dynamics simulation and in vitro assessment of anti-NAFLD efficacy.

Amidst rising global prevalence of metabolic syndrome, the associated risk of non-alcoholic fatty liver disease (NAFLD) is also rapidly increasing. The pathogenesis of NAFLD starts with fat accumulation and progresses through inflammation and fibrotic sequel, often involving complex molecular mechanisms involving de novo lipogenesis. Stearoyl-CoA desaturase 1 (SCD1) enzyme, expressed in liver and adipose tissue, converts saturated fatty acids to monounsaturated fatty acids (MUFAs), contributing to triglyceride and cholesterol ester formation. In this study, potential SCD1 inhibitors were screened using the ZINC database of curated medically-approved drugs by virtual screening, molecular docking, and molecular dynamics simulations. The top-scoring five ligands with strong binding affinity against SCD1 were ZINC000003831151 > ZINC000001540998 > ZINC000003830713 > ZINC000000897251 > ZINC000002005305, which showed stable protein-ligand complexation and favorable pharmacokinetic attributes. The top ligand, Montelukast, was experimentally validated for its pharmacological efficacy in an in vitro cell culture model of steatosis (NAFLD). Montelukast showed a dose-dependent decrease in hepatic fat accumulation, reduced levels of free radicals, and lowered oxidative stress (P < 0.05). These outcomes suggest Montelukast to be a potential SCD1 inhibitor, with anti-NAFLD efficacy. These findings open new avenues for therapeutic development of the top 5 ligands in metabolic disorders involving SCD1.

Sesamin and sesamolin potentially inhibit adipogenesis through downregulating the peroxisome proliferator-activated receptor γ protein expression and activity in 3T3-L1 cells

Sesamin and sesamolin are major sesame lignans that have demonstrated anti-inflammatory, anticancer, and neuroprotective properties and potential benefits in the liver, cardiovascular diseases, and metabolic syndrome. However, despite previous research on their antiobesity effects and underlying mechanisms, a comprehensive investigation of these aspects is still lacking. In this study, we evaluated the regulatory effects of 20 to 80 µM sesamin and sesamolin on adipogenesis in vitro using 3T3-L1 cells as a model cell line. We hypothesized that the lignans would inhibit adipogenic differentiation in 3T3-L1 cells through the regulation of peroxisome proliferator-activated receptor γ (PPARγ). Our data indicate that sesamin and sesamolin inhibited the adipogenic differentiation of 3T3-L1 cells by dose-dependently decreasing lipid accumulation and triglyceride formation. Sesamin and sesamolin reduced the mRNA and protein expression of the adipogenesis-related transcription factors, PPARγ and CCAAT/enhancer-binding protein α, leading to the dose-dependent downregulations of their downstream targets, fatty acid binding protein 4, hormone-sensitive lipase, lipoprotein lipase, and glucose transporter 4. In addition, glucose uptake was dose-dependently attenuated by sesamin and sesamolin in both differentiated 3T3-L1 cells and HepG2 cells. Interestingly, our results suggested that sesamin and sesamolin might directly bind to PPARγ to inhibit its transcriptional activity. Finally, sesamin and sesamolin decreased the phosphorylation of 3 mitogen-activated protein kinase signaling components in differentiated 3T3-L1 cells. Taken together, our findings suggest that sesamin and sesamolin may exhibit antiobesity effects by potentially downregulating PPARγ and its downstream genes through the mitogen-activated protein kinase signaling pathway, offering important insights into the molecular mechanisms underlying the potential antiobesity effects of sesamin and sesamolin.

Abstract A107: Diacylglycerol kinase B mediates radioresistance by regulating mitochondrial lipotoxicity in glioblastoma

Abstract Glioblastoma (GBM) is a malignant primary brain tumor in which the standard treatment, ionizing radiation (IR), achieves a median survival of about 15 months. GBM cells that survive radiotherapy contribute to tumor progression and recurrence with metabolic rewiring. We established radioresistant GBM cells and identified that diacylglycerol kinase B (DGKB), a regulator of the intracellular concentration of diacylglycerol (DAG), is significantly downregulated in these cells. The downregulation of DGKB increases DAG accumulation and reduces fatty acid oxidation, conferring radioresistance by reducing mitochondrial ROS. Diacylglycerol acyltransferase 1 (DGAT1), which catalyzes the formation of triglycerides from DAG, is also increased in radioresistant GBM cells. Genetic inhibition of DGAT1 using miR-3918 mimic suppresses radioresistance. We discover that cladribine, an FDA-approved drug, activates DGKB and inhibits DGAT1 and sensitizes GBM cells to radiotherapy. Taken together, our study demonstrates that DGKB downregulation and DGAT1 upregulation contribute to radioresistance by reducing mitochondrial ROS and suggests DGKB and DGAT1 as therapeutic targets to overcome GBM radioresistance. [This research was supported by National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT (2020M2D9A2094156) and the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (RS-2023-00207904).] Citation Format: Haksoo Lee, Hyunkoo Kang, Eunguk Shin, BuHyun Youn. Diacylglycerol kinase B mediates radioresistance by regulating mitochondrial lipotoxicity in glioblastoma [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A107.

Tld1 is a regulator of triglyceride lipolysis that demarcates a lipid droplet subpopulation.

Cells store lipids in the form of triglyceride (TG) and sterol ester (SE) in lipid droplets (LDs). Distinct pools of LDs exist, but a pervasive question is how proteins localize to and convey functions to LD subsets. Here, we show that the yeast protein YDR275W/Tld1 (for TG-associated LD protein 1) localizes to a subset of TG-containing LDs and reveal it negatively regulates lipolysis. Mechanistically, Tld1 LD targeting requires TG, and it is mediated by two distinct hydrophobic regions (HRs). Molecular dynamics simulations reveal that Tld1's HRs interact with TG on LDs and adopt specific conformations on TG-rich LDs versus SE-rich LDs in yeast and human cells. Tld1-deficient yeast display no defect in LD biogenesis but exhibit elevated TG lipolysis dependent on lipase Tgl3. Remarkably, overexpression of Tld1, but not LD protein Pln1/Pet10, promotes TG accumulation without altering SE pools. Finally, we find that Tld1-deficient cells display altered LD mobilization during extended yeast starvation. We propose that Tld1 senses TG-rich LDs and regulates lipolysis on LD subpopulations.

New Possibilities for Hyposecretory Dry Eye Treatment

Purpose: to evaluate the effectiveness of a fixed combination of 0.24 % hyaluronic acid, carbomer, glycerol and a lipid component in the hyposecretory dry eye treatment. Patients and methods. We examined 35 hyposecretory moderate dry eye (DE) patients in conditions of lipidaquas-mucin deficiency and meibomian gland dysfunction (MGD). All patients included in the study received instillations of a fixed combination of 0.24 % hyaluronic acid (in the form of sodium hyaluronate), carbomer, glycerol and a lipid component (in the form of medium chain triglycerides) — Artelak Night (3 times a day, 2 months). The main criterion for the effectiveness of therapy was the tear film brake up time (TBUT, Norn’s test, s). In addition, the dynamics of the following indicators were taken into account: OSDI (scores), “lid-wiper’ symptom (LWS, scores), lower tear meniscus height (LTMH, μm; OCT, OptoVue), Bijsterveld`s xerosis index (XI, scores; lyssamine green stained). Control points: at inclusion in the study; examination after 1 and 2 months of therapy. Statistics: calculation of the mean and its standard deviation (M ± s); assessment of the reliability of differences in indicators characterizing the state of the ocular surface before and after therapy (Wilcoxon t-test). Results. The patients showed a statistically significant increase in TBUT at the second and third control points, which indicated the effectiveness of DE therapy. The increase in TBUT was accompanied by a significant decrease in the severity of DE subjective symptoms at the same control points (OSDI). On the background of therapy, a trend towards a decrease in LWS was recorded, which was statistically insignificant. Apparently, a significant increase in TBUT and a decrease in OSDI were associated with a significant increase in LTMH at the third control point (decrease in the severity of aqua-deficiency) and a significant decrease in XI at the second and third control points (decrease in the severity of mucose-deficiency). Conclusion. A fixed combination of 0.24 % hyaluronic acid, carbomer, glycerol and a lipid component proved to be effective in the treatment of hyposecretory moderate DE in conditions of lipid-water-mucin deficiency, which was accompanied by a significant increase in TBUT and LTMH, as well as a decrease in OSDI and XI.