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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 -
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 -
Cell Metabolism Jan 2020Oxidized phospholipids (OxPLs), which arise due to oxidative stress, are proinflammatory and proatherogenic, but their roles in non-alcoholic steatohepatitis (NASH) are...
Oxidized phospholipids (OxPLs), which arise due to oxidative stress, are proinflammatory and proatherogenic, but their roles in non-alcoholic steatohepatitis (NASH) are unknown. Here, we show that OxPLs accumulate in human and mouse NASH. Using a transgenic mouse that expresses a functional single-chain variable fragment of E06, a natural antibody that neutralizes OxPLs, we demonstrate the causal role of OxPLs in NASH. Targeting OxPLs in hyperlipidemic Ldlr mice improved multiple aspects of NASH, including steatosis, inflammation, fibrosis, hepatocyte death, and progression to hepatocellular carcinoma. Mechanistically, we found that OxPLs promote ROS accumulation to induce mitochondrial dysfunction in hepatocytes. Neutralizing OxPLs in AMLN-diet-fed Ldlr mice reduced oxidative stress, improved hepatic and adipose-tissue mitochondrial function, and fatty-acid oxidation. These results suggest targeting OxPLs may be an effective therapeutic strategy for NASH.
Topics: Animals; Apoptosis; Carcinoma, Hepatocellular; Diet, High-Fat; Fatty Liver; Gene Ontology; Hepatocytes; Humans; Inflammation; Liver Cirrhosis; Liver Neoplasms; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microscopy, Electron, Transmission; Mitochondria; Non-alcoholic Fatty Liver Disease; Obesity; Oxidation-Reduction; Oxidative Stress; Phospholipids; RNA-Seq; Reactive Oxygen Species; Single-Chain Antibodies
PubMed: 31761566
DOI: 10.1016/j.cmet.2019.10.014 -
Journal of Hepatology Sep 2022Vacuole membrane protein 1 (VMP1) is an endoplasmic reticulum (ER) transmembrane protein that regulates the formation of autophagosomes and lipid droplets. Recent...
BACKGROUND & AIMS
Vacuole membrane protein 1 (VMP1) is an endoplasmic reticulum (ER) transmembrane protein that regulates the formation of autophagosomes and lipid droplets. Recent evidence suggests that VMP1 plays a critical role in lipoprotein secretion in zebra fish and cultured cells. However, the pathophysiological roles and mechanisms by which VMP1 regulates lipoprotein secretion and lipid accumulation in non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are unknown.
METHODS
Liver-specific and hepatocyte-specific Vmp1 knockout mice as well as Vmp1 knock-in mice were generated by crossing Vmp1 or Vmp1 mice with albumin-Cre mice or by injecting AAV8-TBG-cre, respectively. Lipid and energy metabolism in these mice were characterized by metabolomic and transcriptome analyses. Mice with hepatic overexpression of VMP1 who were fed a NASH diet were also characterized.
RESULTS
Hepatocyte-specific deletion of Vmp1 severely impaired VLDL secretion resulting in massive hepatic steatosis, hepatocyte death, inflammation and fibrosis, which are hallmarks of NASH. Mechanistically, loss of Vmp1 led to decreased hepatic levels of phosphatidylcholine and phosphatidylethanolamine as well as to changes in phospholipid composition. Deletion of Vmp1 in mouse liver also led to the accumulation of neutral lipids in the ER bilayer and impaired mitochondrial beta-oxidation. Overexpression of VMP1 ameliorated steatosis in diet-induced NASH by improving VLDL secretion. Importantly, we also showed that decreased liver VMP1 is associated with NAFLD/NASH in humans.
CONCLUSIONS
Our results provide novel insights on the role of VMP1 in regulating hepatic phospholipid synthesis and lipoprotein secretion in the pathogenesis of NAFLD/NASH.
LAY SUMMARY
Non-alcoholic fatty liver disease and its more severe form, non-alcoholic steatohepatitis, are associated with a build-up of fat in the liver (steatosis). However, the exact mechanisms that underly steatosis in patients are not completely understood. Herein, the authors identified that the lack of a protein called VMP1 impairs the secretion and metabolism of fats in the liver and could therefore contribute to the development and progression of non-alcoholic fatty liver disease.
Topics: Animals; Humans; Lipoproteins; Liver; Membrane Proteins; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Phospholipids
PubMed: 35452693
DOI: 10.1016/j.jhep.2022.04.010 -
Hepatology (Baltimore, Md.) Apr 2024NASH, characterized by inflammation and fibrosis, is emerging as a leading etiology of HCC. Lipidomics analyses in the liver have shown that the levels of...
BACKGROUND AND AIMS
NASH, characterized by inflammation and fibrosis, is emerging as a leading etiology of HCC. Lipidomics analyses in the liver have shown that the levels of polyunsaturated phosphatidylcholine (PC) are decreased in patients with NASH, but the roles of membrane PC composition in the pathogenesis of NASH have not been investigated. Lysophosphatidylcholine acyltransferase 3 (LPCAT3), a phospholipid (PL) remodeling enzyme that produces polyunsaturated PLs, is a major determinant of membrane PC content in the liver.
APPROACH AND RESULTS
The expression of LPCAT3 and the correlation between its expression and NASH severity were analyzed in human patient samples. We examined the effect of Lpcat3 deficiency on NASH progression using Lpcat3 liver-specific knockout (LKO) mice. RNA sequencing, lipidomics, and metabolomics were performed in liver samples. Primary hepatocytes and hepatic cell lines were used for in vitro analyses. We showed that LPCAT3 was dramatically suppressed in human NASH livers, and its expression was inversely correlated with NAFLD activity score and fibrosis stage. Loss of Lpcat3 in mouse liver promotes both spontaneous and diet-induced NASH/HCC. Mechanistically, Lpcat3 deficiency enhances reactive oxygen species production due to impaired mitochondrial homeostasis. Loss of Lpcat3 increases inner mitochondrial membrane PL saturation and elevates stress-induced autophagy, resulting in reduced mitochondrial content and increased fragmentation. Furthermore, overexpression of Lpcat3 in the liver ameliorates inflammation and fibrosis of NASH.
CONCLUSIONS
These results demonstrate that membrane PL composition modulates the progression of NASH and that manipulating LPCAT3 expression could be an effective therapeutic for NASH.
Topics: Humans; Animals; Mice; Non-alcoholic Fatty Liver Disease; Phospholipids; Carcinoma, Hepatocellular; Liver Neoplasms; Inflammation; Fibrosis; 1-Acylglycerophosphocholine O-Acyltransferase
PubMed: 36999536
DOI: 10.1097/HEP.0000000000000375 -
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 -
Immunity Apr 2020Innate lymphoid cells (ILCs) play an important role in the control and maintenance of barrier immunity. However, chronic activation of ILCs results in immune-mediated...
Innate lymphoid cells (ILCs) play an important role in the control and maintenance of barrier immunity. However, chronic activation of ILCs results in immune-mediated pathology. Here, we show that tissue-resident type 2 ILCs (ILC2s) display a distinct metabolic signature upon chronic activation. In the context of allergen-driven airway inflammation, ILC2s increase their uptake of both external lipids and glucose. Externally acquired fatty acids are transiently stored in lipid droplets and converted into phospholipids to promote the proliferation of ILC2s. This metabolic program is imprinted by interleukin-33 (IL-33) and regulated by the genes Pparg and Dgat1, which are both controlled by glucose availability and mTOR signaling. Restricting dietary glucose by feeding mice a ketogenic diet largely ablated ILC2-mediated airway inflammation by impairing fatty acid metabolism and the formation of lipid droplets. Together, these results reveal that pathogenic ILC2 responses require lipid metabolism and identify ketogenic diet as a potent intervention strategy to treat airway inflammation.
Topics: Allergens; Alternaria; Animals; Asthma; Cell Lineage; Cytokines; Diacylglycerol O-Acyltransferase; Diet, Ketogenic; Disease Models, Animal; Fatty Acids; Gene Expression Regulation; Glucose; Immunity, Innate; Interleukin-33; Interleukins; Lipid Droplets; Lung; Mice; Mice, Inbred C57BL; Mice, Knockout; PPAR gamma; Papain; Phospholipids; Primary Cell Culture; T-Lymphocyte Subsets; TOR Serine-Threonine Kinases; Thymic Stromal Lymphopoietin
PubMed: 32268121
DOI: 10.1016/j.immuni.2020.03.003 -
Vegan diet in young children remodels metabolism and challenges the statuses of essential nutrients.EMBO Molecular Medicine Feb 2021Vegan diets are gaining popularity, also in families with young children. However, the effects of strict plant-based diets on metabolism and micronutrient status of...
Vegan diets are gaining popularity, also in families with young children. However, the effects of strict plant-based diets on metabolism and micronutrient status of children are unknown. We recruited 40 Finnish children with a median age 3.5 years-vegans, vegetarians, or omnivores from same daycare centers-for a cross-sectional study. They enjoyed nutritionist-planned vegan or omnivore meals in daycare, and the full diets were analyzed with questionnaires and food records. Detailed analysis of serum metabolomics and biomarkers indicated vitamin A insufficiency and border-line sufficient vitamin D in all vegan participants. Their serum total, HDL and LDL cholesterol, essential amino acid, and docosahexaenoic n-3 fatty acid (DHA) levels were markedly low and primary bile acid biosynthesis, and phospholipid balance was distinct from omnivores. Possible combination of low vitamin A and DHA status raise concern for their visual health. Our evidence indicates that (i) vitamin A and D status of vegan children requires special attention; (ii) dietary recommendations for children cannot be extrapolated from adult vegan studies; and (iii) longitudinal studies on infant-onset vegan diets are warranted.
Topics: Adult; Child; Child, Preschool; Cross-Sectional Studies; Diet; Diet, Vegan; Diet, Vegetarian; Humans; Nutrients; Vegetarians
PubMed: 33471422
DOI: 10.15252/emmm.202013492 -
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