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Cell Feb 2024Phospholipids containing a single polyunsaturated fatty acyl tail (PL-PUFAs) are considered the driving force behind ferroptosis, whereas phospholipids with diacyl-PUFA...
Phospholipids containing a single polyunsaturated fatty acyl tail (PL-PUFAs) are considered the driving force behind ferroptosis, whereas phospholipids with diacyl-PUFA tails (PL-PUFAs) have been rarely characterized. Dietary lipids modulate ferroptosis, but the mechanisms governing lipid metabolism and ferroptosis sensitivity are not well understood. Our research revealed a significant accumulation of diacyl-PUFA phosphatidylcholines (PC-PUFAs) following fatty acid or phospholipid treatments, correlating with cancer cell sensitivity to ferroptosis. Depletion of PC-PUFAs occurred in aging and Huntington's disease brain tissue, linking it to ferroptosis. Notably, PC-PUFAs interacted with the mitochondrial electron transport chain, generating reactive oxygen species (ROS) for initiating lipid peroxidation. Mitochondria-targeted antioxidants protected cells from PC-PUFA-induced mitochondrial ROS (mtROS), lipid peroxidation, and cell death. These findings reveal a critical role for PC-PUFAs in controlling mitochondria homeostasis and ferroptosis in various contexts and explain the ferroptosis-modulating mechanisms of free fatty acids. PC-PUFAs may serve as diagnostic and therapeutic targets for modulating ferroptosis.
Topics: Fatty Acids; Ferroptosis; Phosphatidylcholines; Phospholipids; Reactive Oxygen Species; Dietary Fats
PubMed: 38366593
DOI: 10.1016/j.cell.2024.01.030 -
Nutrients Nov 2018Omega-3 fatty acids, one of the key building blocks of cell membranes, have been of particular interest to scientists for many years. However, only a small group of the... (Review)
Review
Omega-3 fatty acids, one of the key building blocks of cell membranes, have been of particular interest to scientists for many years. However, only a small group of the most important omega-3 polyunsaturated fatty acids are considered. This full-length review presents a broad and relatively complete cross-section of knowledge about omega-3 monounsaturated fatty acids, polyunsaturates, and an outline of their modifications. This is important because all these subgroups undoubtedly play an important role in the function of organisms. Some monounsaturated omega-3s are pheromone precursors in insects. Polyunsaturates with a very long chain are commonly found in the central nervous system and mammalian testes, in sponge organisms, and are also immunomodulating agents. Numerous modifications of omega-3 acids are plant hormones. Their chemical structure, chemical binding (in triacylglycerols, phospholipids, and ethyl esters) and bioavailability have been widely discussed indicating a correlation between the last two. Particular attention is paid to the effective methods of supplementation, and a detailed list of sources of omega-3 acids is presented, with meticulous reference to the generally available food. Both the oral and parenteral routes of administration are taken into account, and the omega-3 transport through the blood-brain barrier is mentioned. Having different eating habits in mind, the interactions between food fatty acids intake are discussed. Omega-3 acids are very susceptible to oxidation, and storage conditions often lead to a dramatic increase in this exposure. Therefore, the effect of oxidation on their bioavailability is briefly outlined.
Topics: Animals; Biological Availability; Diet; Fatty Acids, Omega-3; Humans; Phospholipids; Triglycerides
PubMed: 30400360
DOI: 10.3390/nu10111662 -
Nature Feb 2024Mitochondria retain bacterial traits due to their endosymbiotic origin, but host cells do not recognize them as foreign because the organelles are sequestered. However,... (Review)
Review
Mitochondria retain bacterial traits due to their endosymbiotic origin, but host cells do not recognize them as foreign because the organelles are sequestered. However, the regulated release of mitochondrial factors into the cytosol can trigger cell death, innate immunity and inflammation. This selective breakdown in the 2-billion-year-old endosymbiotic relationship enables mitochondria to act as intracellular signalling hubs. Mitochondrial signals include proteins, nucleic acids, phospholipids, metabolites and reactive oxygen species, which have many modes of release from mitochondria, and of decoding in the cytosol and nucleus. Because these mitochondrial signals probably contribute to the homeostatic role of inflammation, dysregulation of these processes may lead to autoimmune and inflammatory diseases. A potential reason for the increased incidence of these diseases may be changes in mitochondrial function and signalling in response to such recent phenomena as obesity, dietary changes and other environmental factors. Focusing on the mixed heritage of mitochondria therefore leads to predictions for future insights, research paths and therapeutic opportunities. Thus, whereas mitochondria can be considered 'the enemy within' the cell, evolution has used this strained relationship in intriguing ways, with increasing evidence pointing to the recent failure of endosymbiosis being critical for the pathogenesis of inflammatory diseases.
Topics: Humans; Autoimmune Diseases; Diet; Homeostasis; Inflammation; Mitochondria; Mitochondrial Proteins; Models, Biological; Nucleic Acids; Obesity; Phospholipids; Reactive Oxygen Species; Symbiosis; Animals
PubMed: 38326590
DOI: 10.1038/s41586-023-06866-z -
Autophagy Jul 2021Recently, we identified a novel mechanism of lipotoxicity in the kidney proximal tubular cells (PTECs); lipid overload stimulates macroautophagy/autophagy for the...
Recently, we identified a novel mechanism of lipotoxicity in the kidney proximal tubular cells (PTECs); lipid overload stimulates macroautophagy/autophagy for the renovation of plasma and organelle membranes to maintain the integrity of the PTECs. However, this autophagic activation places a burden on the lysosomal system, leading to a downstream suppression of autophagy, which manifests as phospholipid accumulation and inadequate acidification in lysosomes. Here, we investigated whether pharmacological correction by eicosapentaenoic acid (EPA) supplementation could restore autophagic flux and alleviate renal lipotoxicity. EPA supplementation to high-fat diet (HFD)-fed mice reduced several hallmarks of lipotoxicity in the PTECs, such as phospholipid accumulation in the lysosome, mitochondrial dysfunction, inflammation, and fibrosis. In addition to improving the metabolic syndrome, EPA alleviated renal lipotoxicity via several mechanisms. EPA supplementation to HFD-fed mice or the isolated PTECs cultured in palmitic acid (PA) restored lysosomal function with significant improvements in the autophagic flux. The PA-induced redistribution of phospholipids from cellular membranes into lysosomes and the HFD-induced accumulation of SQSTM1/p62 (sequestosome 1), an autophagy substrate, during the temporal and genetic ablation of autophagy were significantly reduced by EPA, indicating that EPA attenuated the HFD-mediated increases in autophagy demand. Moreover, a fatty acid pulse-chase assay revealed that EPA promoted lipid droplet (LD) formation and transfer from LDs to the mitochondria for beta-oxidation. Noteworthy, the efficacy of EPA on lipotoxicity is autophagy-dependent and cell-intrinsic. In conclusion, EPA counteracts lipotoxicity in the proximal tubule by alleviating autophagic numbness, making it potentially suitable as a novel treatment for obesity-related kidney diseases. 4-HNE: 4-hydroxy-2-nonenal; ACTB: actin beta; ADGRE1/F4/80: adhesion G protein-coupled receptor E1; ATG: autophagy-related; ATP: adenosine triphosphate; BODIPY: boron-dipyrromethene; BSA: bovine serum albumin; cKO: conditional knockout; CML: N-carboxymethyllysine; COL1A1: collagen type I alpha 1 chain; COX: cytochrome c oxidase; CTRL: control; DGAT: diacylglycerol O-acyltransferase; EPA: eicosapentaenoic acid; FA: fatty acid; FFA: free fatty acid; GFP: green fluorescent protein; HFD: high-fat diet; iKO: inducible knockout; IRI: ischemia-reperfusion injury; LAMP1: lysosomal-associated membrane protein 1; LD: lipid droplet; LRP2: low density lipoprotein receptor-related protein 2; MAP1LC3: microtubule-associated protein 1 light chain 3; MTORC1: mechanistic target of rapamycin kinase complex 1; OA: oleic acid; PAS: periodic-acid Schiff; PPAR: peroxisome proliferator activated receptor; PPARGC1/PGC1: peroxisome proliferator activated receptor, gamma, coactivator 1; PTEC: proximal tubular epithelial cell; ROS: reactive oxygen species; RPS6: ribosomal protein S6; SDH: succinate dehydrogenase complex; SFC/MS/MS: supercritical fluid chromatography triple quadrupole mass spectrometry; SQSTM1/p62: sequestosome 1; TFEB: transcription factor EB; TG: triglyceride; TUNEL: terminal deoxynucleotidyl transferase dUTP nick end labeling.
Topics: Acute Kidney Injury; Animals; Autophagy; Diet, High-Fat; Eicosapentaenoic Acid; Kidney; Kidney Tubules, Proximal; Lysosomes; Mice; Mice, Transgenic; Phospholipids
PubMed: 32546086
DOI: 10.1080/15548627.2020.1782034 -
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 -
International Journal of Biological... 2023Dietary fat intake is positively associated with elevated risk of colorectal cancer (CRC). Currently, clinical treatments remian inadequate bacause of the complex...
Dietary fat intake is positively associated with elevated risk of colorectal cancer (CRC). Currently, clinical treatments remian inadequate bacause of the complex pathogenesis of CRC induced by a high-fat diet (HFD). Mechanistically, imbalances in gut microbiota are associated with HFD-associated colorectal tumourigenesis. Therefore, we investigated the anti-tumor activity of berberine (BBR) in modulating the dysregulated gut microbiota and related metabolites by preforming 16S rDNA sequencing and liquid chromatography/mass spectrometry. As expected, BBR treatment significantly decreased the number of colonic polyps, ameliorated gut barrier disruption, and inhibited colon inflammation and related oncogenic pathways in AOM/DSS-induced CRC model mice fed with an HFD. Furthermore, BBR alleviated gut microbiota dysbiosis and increased the abundance of beneficial gut microorganisms, including and , in HFD-fed CRC mice. In addition, metabolomics analysis demonstrated significantly altered the glycerophospholipid metabolism during the progression of HFD-associated CRC in mice, whereas BBR treatment reverted these changes in glycerophospholipid metabolites, particularly lysophosphatidylcholine (LPC), which was confirmed to promote CRC cell proliferation and ameliorate cell junction impairment. Notably, BBR had no clear anti-tumor effects on HFD-fed CRC model mice with gut microbiota depletion, whereas transplantation of BBR-treated gut microbiota to gut microbiota-depleted CRC mice recapitulated the inhibitory effects of BBR on colorectal tumourigenesis and LPC levels. This study demonstrated that BBR inhibited HFD-associated CRC directly through modulating gut microbiota-regulated LPC levels, thereby providing a promising microbiota-modulating therapeutic strategy for the clinical prevention and treatment of Western diet-associated CRC.
Topics: Animals; Mice; Berberine; Diet, High-Fat; Lysophosphatidylcholines; Gastrointestinal Microbiome; Colorectal Neoplasms; Carcinogenesis; Mice, Inbred C57BL
PubMed: 37151876
DOI: 10.7150/ijbs.81824 -
Nutrients Jul 2023The intake of linoleic acid (LA) has increased dramatically in the standard American diet. LA is generally promoted as supporting human health, but there exists... (Review)
Review
The intake of linoleic acid (LA) has increased dramatically in the standard American diet. LA is generally promoted as supporting human health, but there exists controversy regarding whether the amount of LA currently consumed in the standard American diet supports human health. The goal of this narrative review is to explore the mechanisms that underlie the hypothesis that excessive LA intake may harm human health. While LA is considered to be an essential fatty acid and support health when consumed in modest amounts, an excessive intake of LA leads to the formation of oxidized linoleic acid metabolites (OXLAMs), impairments in mitochondrial function through suboptimal cardiolipin composition, and likely contributes to many chronic diseases that became an epidemic in the 20th century, and whose prevalence continues to increase. The standard American diet comprises 14 to 25 times more omega-6 fatty acids than omega-3 fatty acids, with the majority of omega-6 intake coming from LA. As LA consumption increases, the potential for OXLAM formation also increases. OXLAMs have been associated with various illnesses, including cardiovascular disease, cancer, and Alzheimer's disease, among others. Lowering dietary LA intake can help reduce the production and accumulation of OXLAMs implicated in chronic diseases. While there are other problematic components in the standard American diet, the half-life of LA is approximately two years, which means the damage can be far more persistent than other dietary factors, and the impact of reducing excessive LA intake takes time. Therefore, additional research-evaluating approaches to reduce OXLAM formation and cardiolipin derangements following LA consumption are warranted.
Topics: Humans; Linoleic Acid; Cardiolipins; Chronic Disease; Diet
PubMed: 37513547
DOI: 10.3390/nu15143129 -
Diabetes Care Sep 2023Few trials studied the links of food components in different diets with their induced lipidomic changes and related metabolic outcomes. Thus, we investigated specific... (Randomized Controlled Trial)
Randomized Controlled Trial
Diet-Related Lipidomic Signatures and Changed Type 2 Diabetes Risk in a Randomized Controlled Feeding Study With Mediterranean Diet and Traditional Chinese or Transitional Diets.
OBJECTIVE
Few trials studied the links of food components in different diets with their induced lipidomic changes and related metabolic outcomes. Thus, we investigated specific lipidomic signatures with habitual diets and modified diabetes risk by using a trial and a cohort.
RESEARCH DESIGN AND METHODS
We included 231 Chinese with overweight and prediabetes in a randomized feeding trial with Mediterranean, traditional, or transitional diets (control diet) from February to September 2019. Plasma lipidomic profiles were measured at baseline, third month, and sixth month by high-throughput targeted liquid chromatography-mass spectrometry. Associations of the identified lipids with habitual dietary intakes were examined in another lipidomic database of a Chinese cohort (n = 1,117). The relationships between diet-induced changes of lipidomic species and diabetes risk factors were further investigated through both individual lipids and relevant modules in the trial.
RESULTS
Out of 364 lipidomic species, 26 altered across groups, including 12 triglyceride (TAG) fractions, nine plasmalogens, four phosphatidylcholines (PCs), and one phosphatidylethanolamine. TAG fractions and PCs were associated with habitual fish intake while plasmalogens were associated with red meat intake in the cohort. Of the diet-related lipidomic metabolites, 10 TAG fractions and PC(16:0/22:6) were associated with improved Matsuda index (β = 0.12 to 0.42; PFDR < 0.030). Two plasmalogens were associated with deteriorated fasting glucose (β = 0.29 to 0.31; PFDR < 0.014). Similar results were observed for TAG and plasmalogen related modules.
CONCLUSIONS
These fish- and red meat-related lipidomic signatures sensitively reflected different diets and modified type 2 diabetes risk factors, critical for optimizing dietary patterns.
Topics: Animals; Humans; Diet, Mediterranean; Diabetes Mellitus, Type 2; Lipidomics; East Asian People; Plasmalogens; Diet
PubMed: 37463495
DOI: 10.2337/dc23-0314 -
Advances in Nutrition (Bethesda, Md.) Mar 2022Sphingomyelin (SM) is a widely occurring sphingolipid that is a major plasma membrane constituent. Milk and dairy products are rich SM sources, and human milk has high... (Review)
Review
Sphingomyelin (SM) is a widely occurring sphingolipid that is a major plasma membrane constituent. Milk and dairy products are rich SM sources, and human milk has high SM content. Numerous studies have evaluated the roles of SM in maintaining cell membrane structure and cellular signal transduction. There has been a growing interest in exploring the role of dietary SM, especially from human milk, in imparting health benefits. This review focuses on recent publications regarding SM content in several dietary sources and dietary SM metabolism. SM digestion and absorption are slow and incomplete and mainly occur in the middle sections of the small intestine. This review also evaluates the effect of dietary SM on gut health and cognitive development. Studies indicate that SM may promote gut health by reducing intestinal cholesterol absorption in adults. However, there has been a lack of data supporting clinical trials. An association between milk SM and neural development is evident before childhood. Hence, additional studies and well-designed randomized controlled trials that incorporate dietary SM evaluation, SM metabolism, and its long-term functions on infants and children are required.
Topics: Child; Adult; Infant; Humans; Animals; Sphingomyelins; Diet; Cognition; Milk
PubMed: 34549256
DOI: 10.1093/advances/nmab117 -
Cell Biology and Toxicology Dec 2023We present an integrated analysis of the clinical measurements, immune cells, and plasma lipidomics of 2000 individuals representing different age stages. In the study,...
We present an integrated analysis of the clinical measurements, immune cells, and plasma lipidomics of 2000 individuals representing different age stages. In the study, we explore the interplay of systemic lipids metabolism and circulating immune cells through in-depth analysis of immune cell phenotype and function in peripheral dynamic lipids environment. The population makeup of circulation lymphocytes and lipid metabolites changes dynamically with age. We identified a major shift between young group and middle age group, at which point elevated, immune response is accompanied by the elevation of specific classes of peripheral phospholipids. We tested the effects in mouse model and found that 10-month-dietary added phospholipids induced T-cell senescence. However, the chronic malignant disease, the crosstalk between systemic metabolism and immunity, is completely changed. In cancer patients, the unusual plasma cholesteryl esters emerged, and free fatty acids decreased. The study reveals how immune cell classes and peripheral metabolism coordinate during age acceleration and suggests immune senescence is not isolated, and thus, system effect is the critical point for cell- and function-specific immune-metabolic targeting. • The study identifies a major shift of immune phenotype between young group and middle age group, and the immune response is accompanied by the elevation of specific classes of peripheral phospholipids; • The study suggests potential implications for translational studies such as using metabolic drug to regulate immune activity.
Topics: Middle Aged; Mice; Animals; Humans; Phospholipids; T-Cell Exhaustion; Fatty Acids; Cholesterol Esters
PubMed: 37261679
DOI: 10.1007/s10565-023-09811-y