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Science Advances May 2024Lipid droplets (LDs) comprise a triglyceride core surrounded by a lipid monolayer enriched with proteins, many of which function in LD homeostasis. How proteins are...
Lipid droplets (LDs) comprise a triglyceride core surrounded by a lipid monolayer enriched with proteins, many of which function in LD homeostasis. How proteins are targeted to the growing LD is still unclear. Rab1b, a GTPase regulating secretory transport, was recently associated with targeting proteins to LDs in a Drosophila RNAi screen. LD formation was prevented in human hepatoma cells overexpressing dominant-negative Rab1b. We thus hypothesized that Rab1b recruits lipid-synthesizing enzymes, facilitating LD growth. Here, FRET between diacylglycerol acyltransferase 2 (DGAT2) and Rab1b and activity mutants of the latter demonstrated that Rab1b promotes DGAT2 ER to the LD surface redistribution. Last, alterations in LD metabolism and DGAT2 redistribution, consistent with Rab1b activity, were caused by mutations in the Rab1b-GTPase activating protein TBC1D20 in Warburg Micro syndrome (WARBM) model mice fibroblasts. These data contribute to our understanding of the mechanism of Rab1b in LD homeostasis and WARBM, a devastating autosomal-recessive disorder caused by mutations in TBC1D20.
Topics: Lipid Droplets; Animals; Humans; rab1 GTP-Binding Proteins; Diacylglycerol O-Acyltransferase; Mice; Endoplasmic Reticulum; Mutation; Lipid Metabolism; GTPase-Activating Proteins
PubMed: 38809969
DOI: 10.1126/sciadv.ade7753 -
Food Chemistry Oct 2024Germination of seeds is known to affect the nutritional composition of cold-pressed oils. This study focused on the effects of germination on the antioxidants and...
Germination of seeds is known to affect the nutritional composition of cold-pressed oils. This study focused on the effects of germination on the antioxidants and oxidative stability of linseed and sunflower seed oil. As hypothesized, germination led to increased antioxidant activities and tocopherol, chlorophyll and carotenoid content. Analysis revealed a 37.2 ± 3.5-fold and 11.6 ± 1.5-fold increase in polyphenol content in linseed and sunflower seed oil from germinated seeds, respectively. Using LC-HRMS/MS, profiles with up to 69 polyphenolic substances were identified in germinated seed oils for the first time. Germination promoted lipid hydrolysis, as evidenced by NMR, with overall significant decreases in triacylglycerol content leading to increased diacylglycerol and free fatty acid values. Rancimat measurements predicted a 4.10 ± 0.52-fold longer shelf-life for germinated linseed oil. This study successfully demonstrated the potential of germination to develop PUFA-rich oils with enhanced antioxidant capacity and oxidative stability.
Topics: Germination; Seeds; Oxidation-Reduction; Sunflower Oil; Linseed Oil; Plant Oils; Nutritive Value; Antioxidants; Flax; Helianthus
PubMed: 38805931
DOI: 10.1016/j.foodchem.2024.139790 -
Frontiers in Immunology 2024To describe the lipid metabolic profile of different patients with coronavirus disease 2019 (COVID-19) and contribute new evidence on the progression and severity...
OBJECTIVE
To describe the lipid metabolic profile of different patients with coronavirus disease 2019 (COVID-19) and contribute new evidence on the progression and severity prediction of COVID-19.
METHODS
This case-control study was conducted in Peking University Third Hospital, China. The laboratory-confirmed COVID-19 patients aged ≥18 years old and diagnosed as pneumonia from December 2022 to January 2023 were included. Serum lipids were detected. The discrimination ability was calculated with the area under the curve (AUC). A random forest (RF) model was conducted to determine the significance of different lipids.
RESULTS
Totally, 44 COVID-19 patients were enrolled with 16 mild and 28 severe patients. The top 5 super classes were triacylglycerols (TAG, 55.9%), phosphatidylethanolamines (PE, 10.9%), phosphatidylcholines (PC, 6.8%), diacylglycerols (DAG, 5.9%) and free fatty acids (FFA, 3.6%) among the 778 detected lipids from the serum of COVID-19 patients. Certain lipids, especially lysophosphatidylcholines (LPCs), turned to have significant correlations with certain immune/cytokine indexes. Reduced level of LPC 20:0 was observed in severe patients particularly in acute stage. The AUC of LPC 20:0 reached 0.940 in discriminating mild and severe patients and 0.807 in discriminating acute and recovery stages in the severe patients. The results of RF models also suggested the significance of LPCs in predicting the severity and progression of COVID-19.
CONCLUSION
Lipids probably have the potential to differentiate and forecast the severity, progression, and clinical outcomes of COVID-19 patients, with implications for immune/inflammatory responses. LPC 20:0 might be a potential target in predicting the progression and outcome and the treatment of COVID-19.
Topics: Humans; COVID-19; Male; Female; Middle Aged; Lipidomics; Severity of Illness Index; Case-Control Studies; SARS-CoV-2; Adult; Aged; China; Lipids; Biomarkers; Triglycerides
PubMed: 38799463
DOI: 10.3389/fimmu.2024.1337208 -
Nutrition & Metabolism May 2024Substantial weight loss in people living with type 2 diabetes (T2D) can reduce the need for glucose-lowering medications while concurrently lowering glycemia below the...
A secondary analysis of indices of hepatic and beta cell function following 12 weeks of carbohydrate and energy restriction vs. free-living control in adults with type 2 diabetes.
BACKGROUND
Substantial weight loss in people living with type 2 diabetes (T2D) can reduce the need for glucose-lowering medications while concurrently lowering glycemia below the diagnostic threshold for the disease. Furthermore, weight-loss interventions have also been demonstrated to improve aspects of underlying T2D pathophysiology related to ectopic fat in the liver and pancreatic beta-cell function. As such, the purpose of this secondary analysis was to explore the extent to which a low-carbohydrate and energy-restricted (LCER) diet intervention improves markers of beta-cell stress/function, liver fat accumulation, and metabolic related liver function in people with type 2 diabetes.
METHODS
We conducted secondary analyses of blood samples from a larger pragmatic community-based parallel-group randomized controlled trial involving a 12-week pharmacist implemented LCER diet (Pharm-TCR: <50 g carbohydrates; ~850-1100 kcal/day; n = 20) versus treatment-as-usual (TAU; n = 16). Participants were people with T2D, using ≥ 1 glucose-lowering medication, and a body mass index of ≥ 30 kg/m. Main outcomes were C-peptide to proinsulin ratio, circulating microRNA 375 (miR375), homeostatic model assessment (HOMA) beta-cell function (B), fatty liver index (FLI), hepatic steatosis index (HSI), HOMA insulin resistance (IR), and circulating fetuin-A and fibroblast growth factor 21 (FGF21). Data were analysed using linear regression with baseline as a covariate.
RESULTS
There was no observed change in miR375 (p = 0.42), C-peptide to proinsulin ratio (p = 0.17) or HOMA B (p = 0.15). FLI and HSI were reduced by -25.1 (p < 0.0001) and - 4.9 (p < 0.0001), respectively. HOMA IR was reduced by -46.5% (p = 0.011). FGF21 was reduced by -161.2pg/mL (p = 0.035) with a similar tendency found for fetuin-A (mean difference: -16.7ng/mL; p = 0.11). These improvements in markers of hepatic function were accompanied by reductions in circulating metabolites linked to hepatic insulin resistance (e.g., diacylglycerols, ceramides) in the Pharm TCR group.
CONCLUSIONS
The Pharm-TCR intervention did not improve fasting indices of beta-cell stress; however, markers of liver fat accumulation and and liver function were improved, suggesting that a LCER diet can improve some aspects of the underlying pathophysiology of T2D.
TRIAL REGISTRATION
Clinicaltrials.gov (NCT03181165).
PubMed: 38797835
DOI: 10.1186/s12986-024-00807-x -
Lipids in Health and Disease May 2024Cancer prognosis remains a critical clinical challenge. Lipidomic analysis via mass spectrometry (MS) offers the potential for objective prognostic prediction,... (Review)
Review
Cancer prognosis remains a critical clinical challenge. Lipidomic analysis via mass spectrometry (MS) offers the potential for objective prognostic prediction, leveraging the distinct lipid profiles of cancer patient-derived specimens. This review aims to systematically summarize the application of MS-based lipidomic analysis in prognostic prediction for cancer patients. Our systematic review summarized 38 studies from the past decade that attempted prognostic prediction of cancer patients through lipidomics. Commonly analyzed cancers included colorectal, prostate, and breast cancers. Liquid (serum and urine) and tissue samples were equally used, with liquid chromatography-tandem MS being the most common analytical platform. The most frequently evaluated prognostic outcomes were overall survival, stage, and recurrence. Thirty-eight lipid markers (including phosphatidylcholine, ceramide, triglyceride, lysophosphatidylcholine, sphingomyelin, phosphatidylethanolamine, diacylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylethanolamine, lysophosphatidic acid, dihydroceramide, prostaglandin, sphingosine-1-phosphate, phosphatidylinosito, fatty acid, glucosylceramide and lactosylceramide) were identified as prognostic factors, demonstrating potential for clinical application. In conclusion, the potential for developing lipidomics in cancer prognostic prediction was demonstrated. However, the field is still nascent, necessitating future studies for validating and establishing lipid markers as reliable prognostic tools in clinical practice.
Topics: Humans; Prognosis; Neoplasms; Lipidomics; Biomarkers, Tumor; Mass Spectrometry; Female; Lipids; Male; Breast Neoplasms; Prostatic Neoplasms; Lysophospholipids; Colorectal Neoplasms
PubMed: 38796445
DOI: 10.1186/s12944-024-02121-0 -
European Journal of Pharmaceutics and... Jul 2024Peptides, despite their therapeutic potential, face challenges with undesirable pharmacokinetic (PK) properties and biodistribution, including poor oral absorption and...
Peptides, despite their therapeutic potential, face challenges with undesirable pharmacokinetic (PK) properties and biodistribution, including poor oral absorption and cellular uptake, and short plasma elimination half-lives. Lipidation of peptides is a common strategy to improve their physicochemical and PK properties, making them viable drug candidates. For example, the plasma half-life of peptides has been extended via conjugation to lipids that are proposed to promote binding to serum albumin and thus protect against rapid clearance. Recent work has shown that lipid conjugation to oligodeoxynucleotides, polymers and small molecule drugs results in association not only with albumin, but also with lipoproteins, resulting in half-life prolongation and transport from administration sites via the lymphatics. Enhancing delivery into the lymph increases the efficacy of vaccines and therapeutics with lymphatic targets such as immunotherapies. In this study, the plasma PK, lymphatic uptake, and bioavailability of the glucagon-like peptide-1 (GLP-1) receptor agonist peptides, liraglutide (lipidated) and exenatide (non-lipidated), were investigated following subcutaneous (SC) administration to rats. As expected, liraglutide displayed an apparent prolonged plasma half-life (9.1 versus 1 h), delayed peak plasma concentrations and lower bioavailability (∼10 % versus ∼100 %) compared to exenatide after SC administration. The lymphatic uptake of both peptides was relatively low (<0.5 % of the dose) although lymph to plasma concentration ratios were greater than one for several early timepoints suggesting some direct uptake into lymph. The low lymphatic uptake may be due to the nature of the conjugated lipid (a single-chain C16 palmitic acid in liraglutide) but suggests that other peptides with similar lipid conjugations may also have relatively modest lymphatic uptake. If delivery to the lymph is desired, conjugation to more lipophilic moieties with higher albumin and/or lipoprotein binding efficiencies, such as diacylglycerols, may be appropriate.
Topics: Animals; Exenatide; Liraglutide; Rats; Male; Peptides; Rats, Sprague-Dawley; Lipids; Half-Life; Venoms; Biological Availability; Tissue Distribution; Injections, Subcutaneous; Lymph; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptide 1; Lymphatic System; Hypoglycemic Agents
PubMed: 38789061
DOI: 10.1016/j.ejpb.2024.114339 -
Journal of Dairy Science May 2024Ruminant milk composition can be impacted by many factors, primarily inter-species differences, but also environmental factors (e.g., season, feeding system and feed...
Ruminant milk composition can be impacted by many factors, primarily inter-species differences, but also environmental factors (e.g., season, feeding system and feed composition). Pasture-based feeding systems are known to be influenced by seasonal effects on grass composition. Spring pasture is rich in protein and low in fiber compared with late-season pasture, potentially inducing variability in the composition of some milk metabolites across the season. This study aimed to investigate inter-species and seasonal differences in the milk metabolome across the 3 major commercial ruminant milk species from factories in New Zealand: bovine, caprine and ovine milk. Bovine and caprine raw milk samples were collected monthly for a period of 9 mo (August-April, 2016-2017; bovine n = 41, caprine n = 44 samples); while ovine milk samples were collected for a period of 5 mo (August-January, n = 20 samples). Milk samples were subjected to biphasic extraction, and untargeted metabolite profiling was performed using 2 separate liquid chromatography high-resolution mass spectrometry analytical methods (polar metabolites and lipids). Major differences in milk metabolome were observed between the 3-ruminant species, with 414 of 587 (71%) polar metabolite features and 210 of 233 (87%) lipid features significantly different between species. Significant seasonal trends were observed in the polar metabolite fraction for bovine, caprine and ovine milk (17, 24 and 32 metabolites, respectively), suggesting that the polar metabolite relative intensities of ovine and caprine milk were more susceptible to changes within seasons than bovine milk. There was no significant seasonal difference for the triglycerides (TG) species measured in bovine milk, while 3 and 52 TG species changed in caprine and ovine milk, respectively, across the seasons. Four phosphatidylcholines and 2 phosphatidylethanolamines varied in caprine milk within the season, and 8 diglycerides varied in ovine milk. The inter-species and seasonal metabolite differences reported here provide a knowledge base of components potentially linked to milk physiochemical properties, and potential health benefits of New Zealand pasture-fed dairy ingredients.
PubMed: 38788847
DOI: 10.3168/jds.2023-24595 -
Metabolites Apr 2024Torin1, a selective kinase inhibitor targeting the mammalian target of rapamycin (mTOR), remains widely used in autophagy research due to its potent autophagy-inducing...
Torin1, a selective kinase inhibitor targeting the mammalian target of rapamycin (mTOR), remains widely used in autophagy research due to its potent autophagy-inducing abilities, regardless of its unspecific properties. Recognizing the impact of mTOR inhibition on metabolism, our objective was to develop a reliable and thorough untargeted metabolomics workflow to study torin1-induced metabolic changes in mouse embryonic fibroblast (MEF) cells. Crucially, our quality assurance and quality control (QA/QC) protocols were designed to increase confidence in the reported findings by reducing the likelihood of false positives, including a validation experiment replicating all experimental steps from sample preparation to data analysis. This study investigated the metabolic fingerprint of torin1 exposure by using liquid chromatography-high resolution mass spectrometry (LC-HRMS)-based untargeted metabolomics platforms. Our workflow identified 67 altered metabolites after torin1 exposure, combining univariate and multivariate statistics and the implementation of a validation experiment. In particular, intracellular ceramides, diglycerides, phosphatidylcholines, phosphatidylethanolamines, glutathione, and 5'-methylthioadenosine were downregulated. Lyso-phosphatidylcholines, lyso-phosphatidylethanolamines, glycerophosphocholine, triglycerides, inosine, and hypoxanthine were upregulated. Further biochemical pathway analyses provided deeper insights into the reported changes. Ultimately, our study provides a valuable workflow that can be implemented for future investigations into the effects of other compounds, including more specific autophagy modulators.
PubMed: 38786725
DOI: 10.3390/metabo14050248 -
Biomolecules May 2024Epidemiological and clinical evidence have extensively documented the role of obesity in the development of endometrial cancer. However, the effect of fatty acids on...
Epidemiological and clinical evidence have extensively documented the role of obesity in the development of endometrial cancer. However, the effect of fatty acids on cell growth in endometrial cancer has not been widely studied. Here, we reported that palmitic acid significantly inhibited cell proliferation of endometrial cancer cells and primary cultures of endometrial cancer and reduced tumor growth in a transgenic mouse model of endometrial cancer, in parallel with increased cellular stress and apoptosis and decreased cellular adhesion and invasion. Inhibition of cellular stress by N-acetyl-L-cysteine effectively reversed the effects of palmitic acid on cell proliferation, apoptosis, and invasive capacity in endometrial cancer cells. Palmitic acid increased the intracellular formation of lipid droplets in a time- and dose-dependent manner. Depletion of lipid droplets by blocking DGAT1 and DGAT2 effectively increased the ability of palmitic acid to inhibit cell proliferation and induce cleaved caspase 3 activity. Collectively, this study provides new insight into the effect of palmitic acid on cell proliferation and invasion and the formation of lipid droplets that may have potential clinical relevance in the treatment of obesity-driven endometrial cancer.
Topics: Female; Palmitic Acid; Endometrial Neoplasms; Humans; Lipid Droplets; Animals; Cell Proliferation; Mice; Apoptosis; Cell Line, Tumor; Diacylglycerol O-Acyltransferase; Mice, Transgenic
PubMed: 38786008
DOI: 10.3390/biom14050601 -
Nature Communications May 2024Pancreatic β cells secrete insulin in response to glucose elevation to maintain glucose homeostasis. A complex network of inter-organ communication operates to modulate...
Pancreatic β cells secrete insulin in response to glucose elevation to maintain glucose homeostasis. A complex network of inter-organ communication operates to modulate insulin secretion and regulate glucose levels after a meal. Lipids obtained from diet or generated intracellularly are known to amplify glucose-stimulated insulin secretion, however, the underlying mechanisms are not completely understood. Here, we show that a Drosophila secretory lipase, Vaha (CG8093), is synthesized in the midgut and moves to the brain where it concentrates in the insulin-producing cells in a process requiring Lipid Transfer Particle, a lipoprotein originating in the fat body. In response to dietary fat, Vaha stimulates insulin-like peptide release (ILP), and Vaha deficiency results in reduced circulatory ILP and diabetic features including hyperglycemia and hyperlipidemia. Our findings suggest Vaha functions as a diacylglycerol lipase physiologically, by being a molecular link between dietary fat and lipid amplified insulin secretion in a gut-brain axis.
Topics: Animals; Drosophila Proteins; Brain; Insulin Secretion; Insulin; Drosophila melanogaster; Insulin-Secreting Cells; Brain-Gut Axis; Lipase; Dietary Fats; Glucose; Fat Body; Lipoprotein Lipase; Male
PubMed: 38782979
DOI: 10.1038/s41467-024-48851-8