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Langmuir : the ACS Journal of Surfaces... Oct 2019Novel hydrogel@liposome particles were prepared by pH-triggered molecular gel formation inside of liposomes loaded with a low-molecular weight gelator derived from...
Novel hydrogel@liposome particles were prepared by pH-triggered molecular gel formation inside of liposomes loaded with a low-molecular weight gelator derived from l-valine (). Liposome formation was carried out using l-α-phosphatidylcholine (PC) and cholesterol as components of the lipid bilayer. Molecular hydrogelator and pyranine, a ratiometric fluorescent pH probe, were entrapped in the liposomes at pH 9 and posterior acidification with d-glucono-1,5-lactone to pH 5-6 provoked intraliposomal gel formation. Removal of the lipid bilayer with sodium dodecyl sulfate yielded naked nanogel particles. The systems were characterized by transmission electron microscopy and dynamic light scattering. The hydrogel@liposomes were loaded with doxorubicin, showing a similar release than that observed for liposomes. The hybrid particles described here are the first case of nonpolymeric hydrogel@liposome systems reported. This type of nanocarriers merges the benefits of liposomal vehicles with the inherent stimuli responsiveness and enhanced biocompatibility of hydrogels formed by low-molecular weight molecules, foretelling a potential use in environmentally sensitive drug release.
Topics: Cholesterol; Doxorubicin; Hydrogels; Liposomes; Nanogels; Phosphatidylcholines
PubMed: 31549515
DOI: 10.1021/acs.langmuir.9b02282 -
The Journal of Clinical Investigation Sep 2023The liver has a high demand for phosphatidylcholine (PC), particularly in overnutrition, where reduced phospholipid levels have been implicated in the development of...
The liver has a high demand for phosphatidylcholine (PC), particularly in overnutrition, where reduced phospholipid levels have been implicated in the development of nonalcoholic fatty liver disease (NAFLD). Whether other pathways exist in addition to de novo PC synthesis that contribute to hepatic PC pools remains unknown. Here, we identified the lysophosphatidylcholine (LPC) transporter major facilitator superfamily domain containing 2A (Mfsd2a) as critical for maintaining hepatic phospholipid pools. Hepatic Mfsd2a expression was induced in patients having NAFLD and in mice in response to dietary fat via glucocorticoid receptor action. Mfsd2a liver-specific deficiency in mice (L2aKO) led to a robust nonalcoholic steatohepatitis-like (NASH-like) phenotype within just 2 weeks of dietary fat challenge associated with reduced hepatic phospholipids containing linoleic acid. Reducing dietary choline intake in L2aKO mice exacerbated liver pathology and deficiency of liver phospholipids containing polyunsaturated fatty acids (PUFAs). Treating hepatocytes with LPCs containing oleate and linoleate, two abundant blood-derived LPCs, specifically induced lipid droplet biogenesis and contributed to phospholipid pools, while LPC containing the omega-3 fatty acid docosahexaenoic acid (DHA) promoted lipid droplet formation and suppressed lipogenesis. This study revealed that PUFA-containing LPCs drive hepatic lipid droplet formation, suppress lipogenesis, and sustain hepatic phospholipid pools - processes that are critical for protecting the liver from excess dietary fat.
Topics: Animals; Mice; Phospholipids; Non-alcoholic Fatty Liver Disease; Liver; Lysophospholipids; Phosphatidylcholines; Dietary Fats; Overnutrition
PubMed: 37463052
DOI: 10.1172/JCI171267 -
Cell Metabolism Jun 2023Cellular lipid synthesis and transport are governed by intricate protein networks. Although genetic screening should contribute to deciphering the regulatory networks of...
Cellular lipid synthesis and transport are governed by intricate protein networks. Although genetic screening should contribute to deciphering the regulatory networks of lipid metabolism, technical challenges remain-especially for high-throughput readouts of lipid phenotypes. Here, we coupled organelle-selective click labeling of phosphatidylcholine (PC) with flow cytometry-based CRISPR screening technologies to convert organellar PC phenotypes into a simple fluorescence readout for genome-wide screening. This technique, named O-ClickFC, was successfully applied in genome-scale CRISPR-knockout screens to identify previously reported genes associated with PC synthesis (PCYT1A, ACACA), vesicular membrane trafficking (SEC23B, RAB5C), and non-vesicular transport (PITPNB, STARD7). Moreover, we revealed previously uncharacterized roles of FLVCR1 as a choline uptake facilitator, CHEK1 as a post-translational regulator of the PC-synthetic pathway, and CDC50A as responsible for the translocation of PC to the outside of the plasma membrane bilayer. These findings demonstrate the versatility of O-ClickFC as an unprecedented platform for genetic dissection of cellular lipid metabolism.
Topics: Clustered Regularly Interspaced Short Palindromic Repeats; Flow Cytometry; Lipid Metabolism; Phosphatidylcholines; Organelles; CRISPR-Cas Systems
PubMed: 36917984
DOI: 10.1016/j.cmet.2023.02.014 -
International Journal of Molecular... May 2022Phospholipids represent a crucial component for the structure of cell membranes. Phosphatidylcholine and phosphatidylethanolamine are two phospholipids that comprise the... (Review)
Review
Phospholipids represent a crucial component for the structure of cell membranes. Phosphatidylcholine and phosphatidylethanolamine are two phospholipids that comprise the majority of cell membranes. De novo biosynthesis of phosphatidylcholine and phosphatidylethanolamine occurs via the Kennedy pathway, and perturbations in the regulation of this pathway are linked to a variety of human diseases, including cancer. Altered phosphatidylcholine and phosphatidylethanolamine membrane content, phospholipid metabolite levels, and fatty acid profiles are frequently identified as hallmarks of cancer development and progression. This review summarizes the research on how phospholipid metabolism changes over oncogenic transformation, and how phospholipid profiling can differentiate between human cancer and healthy tissues, with a focus on colorectal cancer, breast cancer, and non-small cell lung cancer. The potential for phospholipids to serve as biomarkers for diagnostics, or as anticancer therapy targets, is also discussed.
Topics: Carcinoma, Non-Small-Cell Lung; Fatty Acids; Humans; Lung Neoplasms; Phosphatidylcholines; Phosphatidylethanolamines; Phospholipids
PubMed: 35563655
DOI: 10.3390/ijms23095266 -
The Journal of Organic Chemistry Jun 2022Lysophosphatidylcholine (LPC) and phosphatidylcholine (PC) are important membrane constituents implicated in signaling and immune regulation. Synthesis of LPCs is...
Lysophosphatidylcholine (LPC) and phosphatidylcholine (PC) are important membrane constituents implicated in signaling and immune regulation. Synthesis of LPCs is challenging due to rapid acyl migration, e.g., induced by chromatography. We here report a highly regioselective synthesis of LPC and mixed PC via an intermediate allowing specific terminal acyl introduction, yielding the pure LPC without chromatography by an exceedingly mild TBS deprotection, using 1 equiv of TFA in aqueous solution. The method enabled the synthesis of glycerol-, acyl-, and choline-labeled LPC.
Topics: Lysophosphatidylcholines; Phosphatidylcholines; Water
PubMed: 35649118
DOI: 10.1021/acs.joc.2c00335 -
Gastroenterology Oct 2023Although transient bacteremia is common during dental and endoscopic procedures, infections developing during sterile diseases like acute pancreatitis (AP) can have...
BACKGROUND & AIMS
Although transient bacteremia is common during dental and endoscopic procedures, infections developing during sterile diseases like acute pancreatitis (AP) can have grave consequences. We examined how impaired bacterial clearance may cause this transition.
METHODS
Blood samples from patients with AP, normal controls, and rodents with pancreatitis or those administered different nonesterified fatty acids (NEFAs) were analyzed for albumin-unbound NEFAs, microbiome, and inflammatory cell injury. Macrophage uptake of unbound NEFAs using a novel coumarin tracer were done and the downstream effects-NEFA-membrane phospholipid (phosphatidylcholine) interactions-were studied on isothermal titration calorimetry.
RESULTS
Patients with infected AP had higher circulating unsaturated NEFAs; unbound NEFAs, including linoleic acid (LA) and oleic acid (OA); higher bacterial 16S DNA; mitochondrial DNA; altered β-diversity; enrichment in Pseudomonadales; and increased annexin V-positive myeloid (CD14) and CD3-positive T cells on admission. These, and increased circulating dead inflammatory cells, were also noted in rodents with unbound, unsaturated NEFAs. Isothermal titration calorimetry showed progressively stronger unbound LA interactions with aqueous media, phosphatidylcholine, cardiolipin, and albumin. Unbound NEFAs were taken into protein-free membranes, cells, and mitochondria, inducing voltage-dependent anion channel oligomerization, reducing ATP, and impairing phagocytosis. These were reversed by albumin. In vivo, unbound LA and OA increased bacterial loads and impaired phagocytosis, causing infection. LA and OA were more potent for these amphipathic interactions than the hydrophobic palmitic acid.
CONCLUSIONS
Release of stored LA and OA can increase their circulating unbound levels and cause amphipathic liponecrosis of immune cells via uptake by membrane phospholipids. This impairs bacterial clearance and causes infection during sterile inflammation.
Topics: Humans; Acute Disease; Pancreatitis; Fatty Acids, Nonesterified; Oleic Acid; Inflammation; Albumins; Phosphatidylcholines
PubMed: 37263302
DOI: 10.1053/j.gastro.2023.05.034 -
Advances in Experimental Medicine and... 2022The sphingomyelin synthase (SMS) gene family has three members: SMS1 and SMS2 have SM synthase activity, while SMS-related protein (SMSr) has no SM synthase activity but...
The sphingomyelin synthase (SMS) gene family has three members: SMS1 and SMS2 have SM synthase activity, while SMS-related protein (SMSr) has no SM synthase activity but has ceramide phosphorylethanolamine (CPE) synthase activity in vitro. Recently, we found that SMS family members are a group of phospholipase Cs (PLC). SMS1 and SMS2 are two phosphatidylcholine (PC)-PLCs and SMSr is a phosphatidylethanolamine (PE)-PLC. SMS family members not only influence SM levels but also influence the levels of diacylglycerol (DAG), PC, PE, and glycosphingolipids, thus influencing cell functions. In this chapter, we will discuss the recent progress in the research field of SMS family and will focus on its impact on metabolic diseases.
Topics: Phosphatidylcholines; Phospholipases; Sphingomyelins; Transferases (Other Substituted Phosphate Groups); Type C Phospholipases
PubMed: 35503176
DOI: 10.1007/978-981-19-0394-6_7 -
Frontiers in Immunology 2022To become resistant, cancer cells need to activate and maintain molecular defense mechanisms that depend on an energy trade-off between resistance and essential... (Review)
Review
To become resistant, cancer cells need to activate and maintain molecular defense mechanisms that depend on an energy trade-off between resistance and essential functions. Metabolic reprogramming has been shown to fuel cell growth and contribute to cancer drug resistance. Recently, changes in lipid metabolism have emerged as an important driver of resistance to anticancer agents. In this review, we highlight the role of choline metabolism with a focus on the phosphatidylcholine cycle in the regulation of resistance to therapy. We analyze the contribution of phosphatidylcholine and its metabolites to intracellular processes of cancer cells, both as the major cell membrane constituents and source of energy. We further extended our discussion about the role of phosphatidylcholine-derived lipid mediators in cellular communication between cancer and immune cells within the tumor microenvironment, as well as their pivotal role in the immune regulation of therapeutic failure. Changes in phosphatidylcholine metabolism are part of an adaptive program activated in response to stress conditions that contribute to cancer therapy resistance and open therapeutic opportunities for treating drug-resistant cancers.
Topics: Antineoplastic Agents; Cell Communication; Humans; Neoplasms; Phosphatidylcholines; Tumor Microenvironment
PubMed: 35250970
DOI: 10.3389/fimmu.2022.768606 -
Progress in Lipid Research Apr 2021Phospholipid biosynthesis is crucial for plant growth and development. It involves attachment of fatty acids to a phospho-diacylglycerol backbone and modification of the... (Review)
Review
Phospholipid biosynthesis is crucial for plant growth and development. It involves attachment of fatty acids to a phospho-diacylglycerol backbone and modification of the phospho-group into an amino alcohol. The biochemistry and molecular biology of the former has been well established, but a number of enzymes responsible for the latter have only recently been cloned and functionally characterized in Arabidopsis and some other model plant species. The metabolism involving the polar head groups of phospholipids established by past biochemical studies can now be validated by available gene knockout models. Moreover, gene knockout studies have revealed emerging functions of phospholipids in regulating plant growth and development. This review aims to revisit the old questions of polar headgroup biosynthesis of plant phosphatidylcholine and phosphatidylethanolamine by giving an overview of recent advances in the field and beyond.
Topics: Arabidopsis; Fatty Acids; Phosphatidylcholines; Phosphatidylethanolamines; Phospholipids
PubMed: 33503494
DOI: 10.1016/j.plipres.2021.101091 -
The American Journal of Clinical... Dec 2019
Topics: Choline; Cognition; Dementia; Humans; Myocardial Ischemia; Phosphatidylcholines; Risk Factors
PubMed: 31536123
DOI: 10.1093/ajcn/nqz244