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Frontiers in Immunology 2023Macrophages are essential for the proper inflammatory and reparative processes that lead to regeneration of skeletal muscle after injury. Recent studies have...
Macrophages are essential for the proper inflammatory and reparative processes that lead to regeneration of skeletal muscle after injury. Recent studies have demonstrated close links between the function of activated macrophages and their cellular metabolism. Sterol regulatory element-binding protein 1 (SREBP1) is a key regulator of lipid metabolism and has been shown to affect the activated states of macrophages. However, its role in tissue repair and regeneration is poorly understood. Here we show that systemic deletion of , encoding SREBP1, or macrophage-specific deletion of , encoding SREBP1a, delays resolution of inflammation and impairs skeletal muscle regeneration after injury. deficiency impairs mitochondrial function in macrophages and suppresses the accumulation of macrophages at sites of muscle injury. Lipidomic analyses showed the reduction of major phospholipid species in muscle myeloid cells. Moreover, diet supplementation with eicosapentaenoic acid restored the accumulation of macrophages and their mitochondrial gene expression and improved muscle regeneration. Collectively, our results demonstrate that SREBP1 in macrophages is essential for repair and regeneration of skeletal muscle after injury and suggest that SREBP1-mediated fatty acid metabolism and phospholipid remodeling are critical for proper macrophage function in tissue repair.
Topics: Macrophages; Muscle, Skeletal; Phospholipids; Regeneration; Sterol Regulatory Element Binding Protein 1; Animals; Mice
PubMed: 38259495
DOI: 10.3389/fimmu.2023.1251784 -
Hepatology Communications Oct 2023The clinical manifestations of Wilson disease (WD) are related to copper accumulation in the liver and the brain, but little is known about other tissue involvement...
BACKGROUND
The clinical manifestations of Wilson disease (WD) are related to copper accumulation in the liver and the brain, but little is known about other tissue involvement regarding metabolic changes in WD. In vitro studies suggested that the loss of intestinal ATP7B affects metabolic dysregulation in WD. We tested this hypothesis by evaluating the gut microbiota and lipidome in 2 mouse models of WD and by characterizing a new mouse model with a targeted deletion of Atp7b in the intestine.
METHODS
Cecal content 16S sequencing and untargeted hepatic and plasma lipidome analyses in the Jackson Laboratory toxic-milk and the Atp7b null global knockout mouse models of WD were profiled and integrated. Intestine-specific Atp7b knockout mice (Atp7bΔIEC) were generated and characterized using targeted lipidome analysis following a high-fat diet challenge.
RESULTS
Gut microbiota diversity was reduced in animal models of WD. Comparative prediction analysis revealed amino acid, carbohydrate, and lipid metabolism functions to be dysregulated in the WD gut microbial metagenome. Liver and plasma lipidomic profiles showed dysregulated triglyceride and diglyceride, phospholipid, and sphingolipid metabolism in WD models. However, Atp7bΔIEC mice did not show gut microbiome differences compared to wild type. When challenged with a high-fat diet, Atp7bΔIEC mice exhibited profound alterations to fatty acid desaturation and sphingolipid metabolism pathways as well as altered APOB48 distribution in intestinal epithelial cells.
CONCLUSIONS
Gut microbiome and lipidome underlie systemic metabolic manifestations in murine WD. Intestine-specific ATP7B deficiency affected both intestinal and systemic response to a high-fat challenge but not the microbiome profile, at least at early stages. WD is a systemic disease in which intestinal-specific ATP7B loss and diet influence the phenotype and the lipidome profile.
Topics: Animals; Mice; Hepatolenticular Degeneration; Lipid Metabolism; Disease Models, Animal; Sphingolipids; Intestines
PubMed: 37695076
DOI: 10.1097/HC9.0000000000000247 -
Journal of Lipid Research Sep 2023Natural variations in the C:C ratio (carbon-13 isotopic abundance [δC]) of the food supply have been used to determine the dietary origin and metabolism of fatty acids,... (Randomized Controlled Trial)
Randomized Controlled Trial
Natural variations in the C:C ratio (carbon-13 isotopic abundance [δC]) of the food supply have been used to determine the dietary origin and metabolism of fatty acids, especially in the n-3 PUFA biosynthesis pathway. However, n-6 PUFA metabolism following linoleic acid (LNA) intake remains under investigation. Here, we sought to use natural variations in the δC signature of dietary oils and fatty fish to analyze n-3 and n-6 PUFA metabolism following dietary changes in LNA and eicosapentaenoic acid (EPA) + DHA in adult humans. Participants with migraine (aged 38.6 ± 2.3 years, 93% female, body mass index of 27.0 ± 1.1 kg/m) were randomly assigned to one of three dietary groups for 16 weeks: 1) low omega-3, high omega-6 (H6), 2) high omega-3, high omega-6 (H3H6), or 3) high omega-3, low omega-6 (H3). Blood was collected at baseline, 4, 10, and 16 weeks. Plasma PUFA concentrations and δC were determined. The H6 intervention exhibited increases in plasma LNA δC signature over time; meanwhile, plasma LNA concentrations were unchanged. No changes in plasma arachidonic acid δC or concentration were observed. Participants on the H3H6 and H3 interventions demonstrated increases in plasma EPA and DHA concentration over time. Plasma δC-EPA increased in total lipids of the H3 group and phospholipids of the H3H6 group compared with baseline. Compound-specific isotope analysis supports a tracer-free technique that can track metabolism of dietary fatty acids in humans, provided that the isotopic signature of the dietary source is sufficiently different from plasma δC.
Topics: Adult; Animals; Humans; Female; Male; Fatty Acids, Omega-6; Fatty Acids, Omega-3; Eicosapentaenoic Acid; Fatty Acids; Phospholipids; Docosahexaenoic Acids
PubMed: 37572791
DOI: 10.1016/j.jlr.2023.100424 -
FASEB Journal : Official Publication of... Nov 2023Previous studies have revealed that membrane phospholipid composition controlled by lysophosphatidylcholine acyltransferase 3 (LPCAT3) is involved in the development of...
Previous studies have revealed that membrane phospholipid composition controlled by lysophosphatidylcholine acyltransferase 3 (LPCAT3) is involved in the development of insulin resistance in type 2 diabetes. In this study, we aimed to investigate the therapeutic potential of targeting Lpcat3 in the treatment of insulin resistance in diabetic mouse models. Lpcat3 expression was suppressed in the whole body by antisense oligonucleotides (ASO) injection or in the liver by adeno-associated virus (AAV)-encoded Cre in high-fat diet (HFD)-induced and genetic ob/ob type 2 diabetic mouse models. Glucose tolerance test (GTT), insulin tolerance test (ITT), fasting blood glucose, and insulin levels were used to assess insulin sensitivity. Lipid levels in the liver and serum were measured. The expression of genes involved in de novo lipogenesis was analyzed by real-time RT-PCR. Metabolic rates were measured by indirect calorimetry using the Comprehensive Lab Animal Monitoring System (CLAMS). Our data demonstrate that acute knockout of hepatic Lpcat3 by AAV-Cre improves both hyperglycemia and hypertriglyceridemia in HFD-fed mice. Similarly, whole-body ablation of Lpcat3 by ASO administration improves obesity and insulin resistance in both HFD-fed and ob/ob mice. These findings demonstrate that targeting LPCAT3 could be a novel therapy for insulin resistance.
Topics: Mice; Animals; Insulin Resistance; Phospholipids; Diabetes Mellitus, Type 2; Liver; Disease Models, Animal; Diet, High-Fat; Insulins; Mice, Inbred C57BL; Insulin; 1-Acylglycerophosphocholine O-Acyltransferase
PubMed: 37823674
DOI: 10.1096/fj.202301122RR -
Molecules (Basel, Switzerland) Aug 2023Aging increases oxidative and inflammatory stress caused by a reduction in metabolism and clearance, thus leading to the development of age-associated diseases. The... (Review)
Review
Aging increases oxidative and inflammatory stress caused by a reduction in metabolism and clearance, thus leading to the development of age-associated diseases. The quality of our daily diet and exercise is important for the prevention of these diseases. Marine resources contain various valuable nutrients, and unique glycerophospholipid plasmalogens are found abundantly in some marine invertebrates, including ascidians. One of the major classes, the ethanolamine class (PlsEtn), exists in a high ratio to phospholipids in the brain and blood, while decreased levels have been reported in patients with age-associated diseases, including Alzheimer's disease. Animal studies have shown that the administration of marine PlsEtn prepared from marine invertebrates improved PlsEtn levels in the body and alleviated inflammation. Animal and human studies have reported that marine PlsEtn ameliorates cognitive impairment. In this review, we highlight the biological significance, relationships with age-associated diseases, food functions, and healthcare materials of plasmalogens based on recent knowledge and discuss the contribution of marine plasmalogens to health maintenance in aging.
Topics: Animals; Humans; Plasmalogens; Brain; Cognitive Dysfunction; Aging; Alzheimer Disease
PubMed: 37687157
DOI: 10.3390/molecules28176328 -
Nature Communications Nov 2023Choline is an essential nutrient, and its deficiency causes steatohepatitis. Dietary phosphatidylcholine (PC) is digested into lysoPC (LPC), glycerophosphocholine, and...
Choline is an essential nutrient, and its deficiency causes steatohepatitis. Dietary phosphatidylcholine (PC) is digested into lysoPC (LPC), glycerophosphocholine, and choline in the intestinal lumen and is the primary source of systemic choline. However, the major PC metabolites absorbed in the intestinal tract remain unidentified. ATP8B1 is a P4-ATPase phospholipid flippase expressed in the apical membrane of the epithelium. Here, we use intestinal epithelial cell (IEC)-specific Atp8b1-knockout (Atp8b1) mice. These mice progress to steatohepatitis by 4 weeks. Metabolomic analysis and cell-based assays show that loss of Atp8b1 in IEC causes LPC malabsorption and thereby hepatic choline deficiency. Feeding choline-supplemented diets to lactating mice achieves complete recovery from steatohepatitis in Atp8b1 mice. Analysis of samples from pediatric patients with ATP8B1 deficiency suggests its translational potential. This study indicates that Atp8b1 regulates hepatic choline levels through intestinal LPC absorption, encouraging the evaluation of choline supplementation therapy for steatohepatitis caused by ATP8B1 dysfunction.
Topics: Female; Humans; Mice; Animals; Child; Choline Deficiency; Lactation; Fatty Liver; Choline; Phosphatidylcholines; Intestinal Diseases; Gastrointestinal Diseases; Adenosine Triphosphatases; Phospholipid Transfer Proteins
PubMed: 37990006
DOI: 10.1038/s41467-023-42424-x -
Biochimie Dec 2023The liver plays a crucial role in lipid metabolism and metabolic homeostasis. Non-Alcoholic Fatty Liver Disease (NAFLD) is the most common chronic liver disease...
The liver plays a crucial role in lipid metabolism and metabolic homeostasis. Non-Alcoholic Fatty Liver Disease (NAFLD) is the most common chronic liver disease worldwide and currently has no specific treatments. Lifestyle modifications such as weight loss, exercise, and dietary changes are recommended to reduce the risk factors associated with the disease. Oxidized cholesterol products, some phospholipids and diacylglycerols can activate inflammatory pathways and contribute to the progression to Non-Alcoholic Steatohepatitis. Monitoring the whole plasma and liver lipidome may provide insights into the onset, development, and prevention of inflammatory-related diseases. As Lipid Droplets (LDs) represent augmented lipid reservoirs in NAFLD, new developments are being made on different therapies focused on LD associated proteins modulation (seipin, PLIN-2), as well as LD lipophagy mechanisms. The information covered in this publication provides an overview of the available research on lipid biomarkers linked to NAFLD and can be used to guide the development of future pharmacological therapies.
Topics: Humans; Non-alcoholic Fatty Liver Disease; Lipid Metabolism; Liver; Cholesterol; Biomarkers
PubMed: 37769937
DOI: 10.1016/j.biochi.2023.09.020 -
Current Opinion in Lipidology Oct 2023To explore the multiple roles that lysophosphatidic acid (LPA) plays in vascular disease and atherosclerosis. (Review)
Review
PURPOSE OF REVIEW
To explore the multiple roles that lysophosphatidic acid (LPA) plays in vascular disease and atherosclerosis.
RECENT FINDINGS
A high-fat high-cholesterol diet decreases antimicrobial activity in the small intestine, which leads to increased levels of bacterial lipopolysaccharide in the mucus of the small intestine and in plasma that increase systemic inflammation, and enhance dyslipidemia and aortic atherosclerosis. Decreasing LPA production in enterocytes reduces the impact of the diet. LPA signaling inhibits glucagon-like peptide 1 secretion, promotes atherosclerosis, increases vessel permeability and infarct volume in stroke, but protects against abdominal aortic aneurysm formation and rupture. Acting through the calpain system in lymphatic endothelial cells, LPA reduces the trafficking of anti-inflammatory Treg lymphocytes, which enhances atherosclerosis. Acting through LPA receptor 1 in cardiac lymphatic endothelial cells and fibroblasts, LPA enhances hypertrophic cardiomyopathy.
SUMMARY
LPA plays multiple roles in vascular disease and atherosclerosis that is cell and context dependent. In some settings LPA promotes these disease processes and in others it inhibits the disease process. Because LPA is so ubiquitous, therapeutic approaches targeting LPA must be as specific as possible for the cells and the context in which the disease process occurs.
Topics: Humans; Endothelial Cells; Lysophospholipids; Atherosclerosis; Intestine, Small
PubMed: 37497844
DOI: 10.1097/MOL.0000000000000890 -
Cell Discovery Nov 2023Lipid droplets (LDs) are dynamic lipid storage organelles that can sense and respond to changes in systemic energy balance. The size and number of LDs are controlled by...
Lipid droplets (LDs) are dynamic lipid storage organelles that can sense and respond to changes in systemic energy balance. The size and number of LDs are controlled by complex and delicate mechanisms, among which, whether and which SNARE proteins mediate LD fusion, and the mechanisms governing this process remain poorly understood. Here we identified a SNARE complex, syntaxin 18 (STX18)-SNAP23-SEC22B, that is recruited to LDs to mediate LD fusion. STX18 targets LDs with its transmembrane domain spanning the phospholipid monolayer twice. STX18-SNAP23-SEC22B complex drives LD fusion in adiposome lipid mixing and content mixing in vitro assays. CIDEC/FSP27 directly binds STX18, SEC22B, and SNAP23, and promotes the lipid mixing of SNAREs-reconstituted adiposomes by promoting LD clustering. Knockdown of STX18 in mouse liver via AAV resulted in smaller liver and reduced LD size under high-fat diet conditions. All these results demonstrate a critical role of the SNARE complex STX18-SNAP23-SEC22B in LD fusion.
PubMed: 37989733
DOI: 10.1038/s41421-023-00613-4 -
Journal of Lipid Research Aug 2023Acute kidney injury (AKI) is a global public health concern with high mortality and morbidity. In ischemic-reperfusion injury (IRI), a main cause of AKI, the brush...
Acute kidney injury (AKI) is a global public health concern with high mortality and morbidity. In ischemic-reperfusion injury (IRI), a main cause of AKI, the brush border membrane of S3 proximal tubules (PT) is lost to the tubular lumen. How injured tubules reconstitute lost membrane lipids during renal recovery is not known. Here, we identified Mfsd2a, a sodium-dependent lysophosphatidylcholine (LPC) transporter, to be expressed specifically in the basolateral membrane of S3 PT. Using an in vivo activity probe for Mfsd2a, transport activity was found to be specific to the S3 PT. Mice with haploinsufficiency of Mfsd2a exhibited delayed recovery of renal function after acute IRI, with depressed urine osmolality and elevated levels of histological markers of damage, fibrosis, and inflammation, findings corroborated by transcriptomic analysis. Lipidomics revealed a deficiency in docosahexaenoic acid (DHA) containing phospholipids in Mfsd2a haploinsufficiency. Treatment of Mfsd2a haploinsufficient mice with LPC-DHA improved renal function and reduced markers of injury, fibrosis, and inflammation. Additionally, LPC-DHA treatment restored S3 brush border membrane architecture and normalized DHA-containing phospholipid content. These findings indicate that Mfsd2a-mediated transport of LPC-DHA is limiting for renal recovery after AKI and suggest that LPC-DHA could be a promising dietary supplement for improving recovery following AKI.
Topics: Mice; Animals; Symporters; Membrane Transport Proteins; Docosahexaenoic Acids; Acute Kidney Injury; Phospholipids; Kidney
PubMed: 37467896
DOI: 10.1016/j.jlr.2023.100416