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Gastroenterology Mar 2022Polygenic and environmental factors are underlying causes of inflammatory bowel disease (IBD). We hypothesized that integration of the genetic loci controlling a...
BACKGROUND & AIMS
Polygenic and environmental factors are underlying causes of inflammatory bowel disease (IBD). We hypothesized that integration of the genetic loci controlling a metabolite's abundance, with known IBD genetic susceptibility loci, may help resolve metabolic drivers of IBD.
METHODS
We measured the levels of 1300 metabolites in the serum of 484 patients with ulcerative colitis (UC) and 464 patients with Crohn's disease (CD) and 365 controls. Differential metabolite abundance was determined for disease status, subtype, clinical and endoscopic disease activity, as well as IBD phenotype including disease behavior, location, and extent. To inform on the genetic basis underlying metabolic diversity, we integrated metabolite and genomic data. Genetic colocalization and Mendelian randomization analyses were performed using known IBD risk loci to explore whether any metabolite was causally associated with IBD.
RESULTS
We found 173 genetically controlled metabolites (metabolite quantitative trait loci, 9 novel) within 63 non-overlapping loci (7 novel). Furthermore, several metabolites significantly associated with IBD disease status and activity as defined using clinical and endoscopic indexes. This constitutes a resource for biomarker discovery and IBD biology insights. Using this resource, we show that a novel metabolite quantitative trait locus for serum butyrate levels containing ACADS was not supported as causal for IBD; replicate the association of serum omega-6 containing lipids with the fatty acid desaturase 1/2 locus and identify these metabolites as causal for CD through Mendelian randomization; and validate a novel association of serum plasmalogen and TMEM229B, which was predicted as causal for CD.
CONCLUSIONS
An exploratory analysis combining genetics and unbiased serum metabolome surveys can reveal novel biomarkers of disease activity and potential mediators of pathology in IBD.
Topics: Acyl-CoA Dehydrogenase; Adolescent; Adult; Aged; Aged, 80 and over; Biomarkers; Butyrates; Case-Control Studies; Child; Child, Preschool; Colitis, Ulcerative; Crohn Disease; Cross-Sectional Studies; Feces; Female; Genome-Wide Association Study; Genotype; HEK293 Cells; Humans; Male; Mendelian Randomization Analysis; Metabolome; Middle Aged; Plasmalogens; Quantitative Trait Loci; Severity of Illness Index; Young Adult
PubMed: 34780722
DOI: 10.1053/j.gastro.2021.11.015 -
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 -
Nature Communications Oct 2023Mitochondrial function is vital for energy metabolism in thermogenic adipocytes. Impaired mitochondrial bioenergetics in brown adipocytes are linked to disrupted...
Mitochondrial function is vital for energy metabolism in thermogenic adipocytes. Impaired mitochondrial bioenergetics in brown adipocytes are linked to disrupted thermogenesis and energy balance in obesity and aging. Phospholipid cardiolipin (CL) and phosphatidic acid (PA) jointly regulate mitochondrial membrane architecture and dynamics, with mitochondria-associated endoplasmic reticulum membranes (MAMs) serving as the platform for phospholipid biosynthesis and metabolism. However, little is known about the regulators of MAM phospholipid metabolism and their connection to mitochondrial function. We discover that LCN2 is a PA binding protein recruited to the MAM during inflammation and metabolic stimulation. Lcn2 deficiency disrupts mitochondrial fusion-fission balance and alters the acyl-chain composition of mitochondrial phospholipids in brown adipose tissue (BAT) of male mice. Lcn2 KO male mice exhibit an increase in the levels of CLs containing long-chain polyunsaturated fatty acids (LC-PUFA), a decrease in CLs containing monounsaturated fatty acids, resulting in mitochondrial dysfunction. This dysfunction triggers compensatory activation of peroxisomal function and the biosynthesis of LC-PUFA-containing plasmalogens in BAT. Additionally, Lcn2 deficiency alters PA production, correlating with changes in PA-regulated phospholipid-metabolizing enzymes and the mTOR signaling pathway. In conclusion, LCN2 plays a critical role in the acyl-chain remodeling of phospholipids and mitochondrial bioenergetics by regulating PA production and its function in activating signaling pathways.
Topics: Animals; Male; Mice; Adipocytes, Brown; Adipose Tissue, Brown; Lipocalin-2; Mice, Inbred C57BL; Mice, Knockout; Mitochondria; Plasmalogens; Thermogenesis
PubMed: 37872178
DOI: 10.1038/s41467-023-42473-2 -
Metabolites Feb 2021Thermogenesis is an energy demanding process by which endotherms produce heat to maintain their body temperature in response to cold exposure. Mitochondria in the brown... (Review)
Review
Thermogenesis is an energy demanding process by which endotherms produce heat to maintain their body temperature in response to cold exposure. Mitochondria in the brown and beige adipocytes play a key role in thermogenesis, as the site for uncoupling protein 1 (UCP1), which allows for the diffusion of protons through the mitochondrial inner membrane to produce heat. To support this energy demanding process, the mitochondria in brown and beige adipocytes increase oxidation of glucose, amino acids, and lipids. This review article explores the various mitochondria-produced and processed lipids that regulate thermogenesis including cardiolipins, free fatty acids, and acylcarnitines. These lipids play a number of roles in thermogenic adipose tissue including structural support of UCP1, transcriptional regulation, fuel source, and activation of cell signaling cascades.
PubMed: 33671745
DOI: 10.3390/metabo11020124 -
The Journal of Biological Chemistry Mar 2020An early exposure to lipid biochemistry in the laboratory of Konrad Bloch resulted in a fascination with the biosynthesis, structures, and functions of bacterial lipids....
An early exposure to lipid biochemistry in the laboratory of Konrad Bloch resulted in a fascination with the biosynthesis, structures, and functions of bacterial lipids. The discovery of plasmalogens (1-alk-1'-enyl, 2-acyl phospholipids) in anaerobic Gram-positive bacteria led to studies on the physical chemistry of these lipids and the cellular regulation of membrane lipid polymorphism in bacteria. Later studies in several laboratories showed that the formation of the alk-1-enyl ether bond involves an aerobic process in animal cells and thus is fundamentally different from that in anaerobic organisms. Our work provides evidence for an anaerobic process in which plasmalogens are formed from their corresponding diacyl lipids. Studies on the roles of phospholipases in revealed distinctions between its phospholipases and those previously discovered in other bacteria and showed how the enzymes are uniquely fitted to the intracellular lifestyle of this significant human pathogen.
Topics: Anaerobiosis; Bacteria, Anaerobic; Fatty Acids; Gram-Positive Bacteria; Lipids; Phosphatidylethanolamines; Plasmalogens
PubMed: 32221031
DOI: 10.1074/jbc.X120.013022 -
Frontiers in Physiology 2021It is becoming widely acknowledged that lipids play key roles in cellular function, regulating a variety of biological processes. Lately, a subclass of... (Review)
Review
It is becoming widely acknowledged that lipids play key roles in cellular function, regulating a variety of biological processes. Lately, a subclass of glycerophospholipids, namely plasmalogens, has received increased attention due to their association with several degenerative and metabolic disorders as well as aging. All these pathophysiological conditions involve chronic inflammatory processes, which have been linked with decreased levels of plasmalogens. Currently, there is a lack of full understanding of the molecular mechanisms governing the association of plasmalogens with inflammation. However, it has been shown that in inflammatory processes, plasmalogens could trigger either an anti- or pro-inflammation response. While the anti-inflammatory response seems to be linked to the entire plasmalogen molecule, its pro-inflammatory response seems to be associated with plasmalogen hydrolysis, ., the release of arachidonic acid, which, in turn, serves as a precursor to produce pro-inflammatory lipid mediators. Moreover, as plasmalogens comprise a large fraction of the total lipids in humans, changes in their levels have been shown to change membrane properties and, therefore, signaling pathways involved in the inflammatory cascade. Restoring plasmalogen levels by use of plasmalogen replacement therapy has been shown to be a successful anti-inflammatory strategy as well as ameliorating several pathological hallmarks of these diseases. The purpose of this review is to highlight the emerging role of plasmalogens in chronic inflammatory disorders as well as the promising role of plasmalogen replacement therapy in the treatment of these pathologies.
PubMed: 34744771
DOI: 10.3389/fphys.2021.730829 -
Food Science and Biotechnology Sep 2022Egg yolk contains very high levels of lipids, which comprise 33% of whole egg yolk. Although triglyceride is the main lipid, egg yolk is the richest source of... (Review)
Review
Egg yolk contains very high levels of lipids, which comprise 33% of whole egg yolk. Although triglyceride is the main lipid, egg yolk is the richest source of phospholipids and cholesterol in nature. The egg yolk phospholipids have a unique composition with high levels of phosphatidylcholine followed by phosphatidylethanolamine, sphingomyelin, plasmalogen, and phosphatidylinositol. All the egg yolk lipids are embedded inside the HDL and LDL micelles or granular particles. Egg yolk lipids can be easily extracted using solvents or supercritical extraction methods but their commercial applications of egg yolk lipids are limited. Egg yolk lipids have excellent potential as a food ingredient or cosmeceutical, pharmaceutical, and nutraceutical agents because they have excellent functional and biological characteristics. This review summarizes the current knowledge on egg yolk lipids' extraction methods and functions and discusses their current and future use, which will be important to increase the use and value of the egg.
PubMed: 35992319
DOI: 10.1007/s10068-022-01138-4 -
Nature Communications Jul 2022Dysregulation of adipose tissue plasmalogen metabolism is associated with obesity-related metabolic diseases. We report that feeding mice a high-fat diet reduces adipose...
Dysregulation of adipose tissue plasmalogen metabolism is associated with obesity-related metabolic diseases. We report that feeding mice a high-fat diet reduces adipose tissue lysoplasmalogen levels and increases transmembrane protein 86 A (TMEM86A), a putative lysoplasmalogenase. Untargeted lipidomic analysis demonstrates that adipocyte-specific TMEM86A-knockout (AKO) increases lysoplasmalogen content in adipose tissue, including plasmenyl lysophosphatidylethanolamine 18:0 (LPE P-18:0). Surprisingly, TMEM86A AKO increases protein kinase A signalling pathways owing to inhibition of phosphodiesterase 3B and elevation of cyclic adenosine monophosphate. TMEM86A AKO upregulates mitochondrial oxidative metabolism, elevates energy expenditure, and protects mice from metabolic dysfunction induced by high-fat feeding. Importantly, the effects of TMEM86A AKO are largely reproduced in vitro and in vivo by LPE P-18:0 supplementation. LPE P-18:0 levels are significantly lower in adipose tissue of human patients with obesity, suggesting that TMEM86A inhibition or lysoplasmalogen supplementation might be therapeutic approaches for preventing or treating obesity-related metabolic diseases.
Topics: Adipocytes; Animals; Cyclic AMP-Dependent Protein Kinases; Diet, High-Fat; Energy Metabolism; Homeostasis; Humans; Hydrolases; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity; Plasmalogens; Thermogenesis
PubMed: 35835749
DOI: 10.1038/s41467-022-31805-3 -
Brain Research Bulletin Mar 2023Plasmalogens are a unique family of cellular glycerophospholipids that contain a vinyl-ether bond. Synthesis of plasmalogens is initiated in peroxisomes and completed in... (Review)
Review
Plasmalogens are a unique family of cellular glycerophospholipids that contain a vinyl-ether bond. Synthesis of plasmalogens is initiated in peroxisomes and completed in the endoplasmic reticulum. The absence of plasmalogens in several organs of patients with deficiency in peroxisome biogenesis suggests that de novo synthesis of plasmalogens contributes significantly to plasmalogen homeostasis in humans. Plasmalogen biosynthesis is spatiotemporally regulated by a feedback mechanism that senses the amount of plasmalogens in the inner leaflet of the plasma membrane and regulates the stability of fatty acyl-CoA reductase 1 (FAR1), the rate-limiting enzyme for plasmalogen biosynthesis. Dysregulation of plasmalogen synthesis impairs cholesterol synthesis in cells and brain, resulting in the reduced expression of genes such as mRNA encoding myelin basic protein, a phenotype found in the cerebellum of plasmalogen-deficient mice. In this review, we summarize the current knowledge of molecular mechanisms underlying the regulation of plasmalogen biosynthesis and the link between plasmalogen homeostasis and cholesterol biosynthesis, and address the pathogenesis of impaired plasmalogen homeostasis in rodent and humans.
Topics: Humans; Animals; Mice; Plasmalogens; Homeostasis; Cholesterol; Mammals
PubMed: 36720320
DOI: 10.1016/j.brainresbull.2023.01.011 -
Biochimica Et Biophysica Acta.... Sep 2021Studies of the lipidomes of twenty-one species of clostridia have revealed considerable diversity. Even among those species now defined as Clostridium sensu stricto,... (Review)
Review
Studies of the lipidomes of twenty-one species of clostridia have revealed considerable diversity. Even among those species now defined as Clostridium sensu stricto, which are related to Clostridium butyricum, the type species, lipid analysis has shown that a number of distinct clades have characteristic polar lipids. All species of Clostridium sensu stricto have phosphatidylethanolamine, phosphatidylglycerol and cardiolipin which are present as all acyl or alk-1'-enyl acyl (plasmalogen) species. In addition, almost every clade has specialized polar lipids. For example, the group closely related to Clostridium beijerinckii and several other solventogenic species has glycerol acetals of plasmenylethanolamine, which protects the membrane bilayer arrangement when the lipids are highly unsaturated or in the presence of solvents. The group related to Clostridium novyi has aminoacyl-phosphatidylglycerol, which protects these pathogens from cationic antimicrobial peptides (CAMPs) of innate immunity. Clostridium botulinum species, which fall into several groups, align with these clades, and have the same specific lipids. This review will present the current state of knowledge on clostridial lipids.
Topics: Clostridium; Lipidomics
PubMed: 33974975
DOI: 10.1016/j.bbalip.2021.158966