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Nature Sep 2023Triacylglycerols (TAGs) are the main source of stored energy in the body, providing an important substrate pool for mitochondrial beta-oxidation. Imbalances in the...
Triacylglycerols (TAGs) are the main source of stored energy in the body, providing an important substrate pool for mitochondrial beta-oxidation. Imbalances in the amount of TAGs are associated with obesity, cardiac disease and various other pathologies. In humans, TAGs are synthesized from excess, coenzyme A-conjugated fatty acids by diacylglycerol O-acyltransferases (DGAT1 and DGAT2). In other organisms, this activity is complemented by additional enzymes, but whether such alternative pathways exist in humans remains unknown. Here we disrupt the DGAT pathway in haploid human cells and use iterative genetics to reveal an unrelated TAG-synthesizing system composed of a protein we called DIESL (also known as TMEM68, an acyltransferase of previously unknown function) and its regulator TMX1. Mechanistically, TMX1 binds to and controls DIESL at the endoplasmic reticulum, and loss of TMX1 leads to the unconstrained formation of DIESL-dependent lipid droplets. DIESL is an autonomous TAG synthase, and expression of human DIESL in Escherichia coli endows this organism with the ability to synthesize TAG. Although both DIESL and the DGATs function as diacylglycerol acyltransferases, they contribute to the cellular TAG pool under specific conditions. Functionally, DIESL synthesizes TAG at the expense of membrane phospholipids and maintains mitochondrial function during periods of extracellular lipid starvation. In mice, DIESL deficiency impedes rapid postnatal growth and affects energy homeostasis during changes in nutrient availability. We have therefore identified an alternative TAG biosynthetic pathway driven by DIESL under potent control by TMX1.
Topics: Animals; Humans; Mice; Acyltransferases; Coenzyme A; Diacylglycerol O-Acyltransferase; Escherichia coli; Homeostasis; Triglycerides; Energy Metabolism; Nutrients; Fatty Acids
PubMed: 37648867
DOI: 10.1038/s41586-023-06497-4 -
BMJ (Clinical Research Ed.) Sep 2023To assess the associations between exposure to food additive emulsifiers and risk of cardiovascular disease (CVD).
OBJECTIVE
To assess the associations between exposure to food additive emulsifiers and risk of cardiovascular disease (CVD).
DESIGN
Prospective cohort study.
SETTING
French NutriNet-Santé study, 2009-21.
PARTICIPANTS
95 442 adults (>18 years) without prevalent CVD who completed at least three 24 hour dietary records during the first two years of follow-up.
MAIN OUTCOME MEASURES
Associations between intake of food additive emulsifiers (continuous (mg/day)) and risk of CVD, coronary heart disease, and cerebrovascular disease characterised using multivariable proportional hazard Cox models to compute hazard ratios for each additional standard deviation (SD) of emulsifier intake, along with 95% confidence intervals.
RESULTS
Mean age was 43.1 (SD 14.5) years, and 79.0% (n=75 390) of participants were women. During follow-up (median 7.4 years), 1995 incident CVD, 1044 coronary heart disease, and 974 cerebrovascular disease events were diagnosed. Higher intake of celluloses (E460-E468) was found to be positively associated with higher risks of CVD (hazard ratio for an increase of 1 standard deviation 1.05, 95% confidence interval 1.02 to 1.09, P=0.003) and coronary heart disease (1.07, 1.02 to 1.12, P=0.004). Specifically, higher cellulose E460 intake was linked to higher risks of CVD (1.05, 1.01 to 1.09, P=0.007) and coronary heart disease (1.07, 1.02 to 1.12, P=0.005), and higher intake of carboxymethylcellulose (E466) was associated with higher risks of CVD (1.03, 1.01 to 1.05, P=0.004) and coronary heart disease (1.04, 1.02 to 1.06, P=0.001). Additionally, higher intakes of monoglycerides and diglycerides of fatty acids (E471 and E472) were associated with higher risks of all outcomes. Among these emulsifiers, lactic ester of monoglycerides and diglycerides of fatty acids (E472b) was associated with higher risks of CVD (1.06, 1.02 to 1.10, P=0.002) and cerebrovascular disease (1.11, 1.06 to 1.16, P<0.001), and citric acid ester of monoglycerides and diglycerides of fatty acids (E472c) was associated with higher risks of CVD (1.04, 1.02 to 1.07, P=0.004) and coronary heart disease (1.06, 1.03 to 1.09, P<0.001). High intake of trisodium phosphate (E339) was associated with an increased risk of coronary heart disease (1.06, 1.00 to 1.12, P=0.03). Sensitivity analyses showed consistent associations.
CONCLUSION
This study found positive associations between risk of CVD and intake of five individual and two groups of food additive emulsifiers widely used in industrial foods.
TRIAL REGISTRATION
ClinicalTrials.gov NCT03335644.
Topics: Adult; Humans; Female; Male; Cardiovascular Diseases; Food Additives; Diglycerides; Monoglycerides; Prospective Studies; Cellulose; Esters; Fatty Acids
PubMed: 37673430
DOI: 10.1136/bmj-2023-076058 -
Marine Drugs Oct 2023Reef-building corals, recognized as cornerstone species in marine ecosystems, captivate with their unique duality as both symbiotic partners and autotrophic entities.... (Review)
Review
Reef-building corals, recognized as cornerstone species in marine ecosystems, captivate with their unique duality as both symbiotic partners and autotrophic entities. Beyond their ecological prominence, these corals produce a diverse array of secondary metabolites, many of which are poised to revolutionize the domains of pharmacology and medicine. This exhaustive review delves deeply into the multifaceted world of coral-derived lipids, highlighting both ubiquitous and rare forms. Within this spectrum, we navigate through a myriad of fatty acids and their acyl derivatives, encompassing waxes, sterol esters, triacylglycerols, mono-akyl-diacylglycerols, and an array of polar lipids such as betaine lipids, glycolipids, sphingolipids, phospholipids, and phosphonolipids. We offer a comprehensive exploration of the intricate biochemical variety of these lipids, related fatty acids, prostaglandins, and both cyclic and acyclic oxilipins. Additionally, the review provides insights into the chemotaxonomy of these compounds, illuminating the fatty acid synthesis routes inherent in corals. Of particular interest is the symbiotic bond many coral species nurture with dinoflagellates from the Symbiodinium group; their lipid and fatty acid profiles are also detailed in this discourse. This exploration accentuates the vast potential and intricacy of coral lipids and underscores their profound relevance in scientific endeavors.
Topics: Animals; Anthozoa; Ecosystem; Fatty Acids; Prostaglandins; Coral Reefs; Dinoflagellida; Symbiosis
PubMed: 37888474
DOI: 10.3390/md21100539 -
Science Translational Medicine Oct 2023Programmed cell death protein 1 (PD-1) immune checkpoint blockade therapy has revolutionized cancer treatment. Although PD-1 blockade is effective in a subset of...
Programmed cell death protein 1 (PD-1) immune checkpoint blockade therapy has revolutionized cancer treatment. Although PD-1 blockade is effective in a subset of patients with cancer, many fail to respond because of either primary or acquired resistance. Thus, next-generation strategies are needed to expand the depth and breadth of clinical responses. Toward this end, we designed a human primary T cell phenotypic high-throughput screening strategy to identify small molecules with distinct and complementary mechanisms of action to PD-1 checkpoint blockade. Through these efforts, we selected and optimized a chemical series that showed robust potentiation of T cell activation and combinatorial activity with αPD-1 blockade. Target identification was facilitated by chemical proteomic profiling with a lipid-based photoaffinity probe, which displayed enhanced binding to diacylglycerol kinase α (DGKα) in the presence of the active compound, a phenomenon that correlated with the translocation of DGKα to the plasma membrane. We further found that optimized leads within this chemical series were potent and selective inhibitors of both DGKα and DGKζ, lipid kinases that constitute an intracellular T cell checkpoint that blunts T cell signaling through diacylglycerol metabolism. We show that dual DGKα/ζ inhibition amplified suboptimal T cell receptor signaling mediated by low-affinity antigen presentation and low major histocompatibility complex class I expression on tumor cells, both hallmarks of resistance to PD-1 blockade. In addition, DGKα/ζ inhibitors combined with αPD-1 therapy to elicit robust tumor regression in syngeneic mouse tumor models. Together, these findings support targeting DGKα/ζ as a next-generation T cell immune checkpoint strategy.
Topics: Mice; Animals; Humans; Programmed Cell Death 1 Receptor; Proteomics; Diacylglycerol Kinase; T-Lymphocytes; Neoplasms; Lipids
PubMed: 37878674
DOI: 10.1126/scitranslmed.adh1892 -
Cell Feb 2024Phosphatidic acid (PA) and reactive oxygen species (ROS) are crucial cellular messengers mediating diverse signaling processes in metazoans and plants. How PA...
Phosphatidic acid (PA) and reactive oxygen species (ROS) are crucial cellular messengers mediating diverse signaling processes in metazoans and plants. How PA homeostasis is tightly regulated and intertwined with ROS signaling upon immune elicitation remains elusive. We report here that Arabidopsis diacylglycerol kinase 5 (DGK5) regulates plant pattern-triggered immunity (PTI) and effector-triggered immunity (ETI). The pattern recognition receptor (PRR)-associated kinase BIK1 phosphorylates DGK5 at Ser-506, leading to a rapid PA burst and activation of plant immunity, whereas PRR-activated intracellular MPK4 phosphorylates DGK5 at Thr-446, which subsequently suppresses DGK5 activity and PA production, resulting in attenuated plant immunity. PA binds and stabilizes the NADPH oxidase RESPIRATORY BURST OXIDASE HOMOLOG D (RBOHD), regulating ROS production in plant PTI and ETI, and their potentiation. Our data indicate that distinct phosphorylation of DGK5 by PRR-activated BIK1 and MPK4 balances the homeostasis of cellular PA burst that regulates ROS generation in coordinating two branches of plant immunity.
Topics: Arabidopsis; Arabidopsis Proteins; Diacylglycerol Kinase; NADPH Oxidases; Phosphatidic Acids; Phosphorylation; Plant Immunity; Protein Serine-Threonine Kinases; Reactive Oxygen Species; Receptors, Pattern Recognition
PubMed: 38244548
DOI: 10.1016/j.cell.2023.12.030 -
Cell Metabolism Mar 2024Diacylglycerol acyltransferase 2 (DGAT2) catalyzes the final step of triglyceride (TG) synthesis. DGAT2 deletion in mice lowers liver TGs, and DGAT2 inhibitors are under...
Diacylglycerol acyltransferase 2 (DGAT2) catalyzes the final step of triglyceride (TG) synthesis. DGAT2 deletion in mice lowers liver TGs, and DGAT2 inhibitors are under investigation for the treatment of fatty liver disease. Here, we show that DGAT2 inhibition also suppressed SREBP-1 cleavage, reduced fatty acid synthesis, and lowered TG accumulation and secretion from liver. DGAT2 inhibition increased phosphatidylethanolamine (PE) levels in the endoplasmic reticulum (ER) and inhibited SREBP-1 cleavage, while DGAT2 overexpression lowered ER PE concentrations and increased SREBP-1 cleavage in vivo. ER enrichment with PE blocked SREBP-1 cleavage independent of Insigs, which are ER proteins that normally retain SREBPs in the ER. Thus, inhibition of DGAT2 shunted diacylglycerol into phospholipid synthesis, increasing the PE content of the ER, resulting in reduced SREBP-1 cleavage and less hepatic steatosis. This study reveals a new mechanism that regulates SREBP-1 activation and lipogenesis that is independent of sterols and SREBP-2 in liver.
Topics: Animals; Mice; Diacylglycerol O-Acyltransferase; Endoplasmic Reticulum; Liver; Non-alcoholic Fatty Liver Disease; Phosphatidylethanolamines; Sterol Regulatory Element Binding Protein 1; Triglycerides
PubMed: 38340721
DOI: 10.1016/j.cmet.2024.01.011 -
Nephrology (Carlton, Vic.) Oct 2023A limited number of cases of thrombotic microangiopathy (TMA) have previously been reported in association with COVID-19. Our report describes two cases of TMA...
A limited number of cases of thrombotic microangiopathy (TMA) have previously been reported in association with COVID-19. Our report describes two cases of TMA associated with COVID-19, one of which was successfully treated with eculizumab. The first case was a 23-month-old girl, and the second case was a 9-month-old boy. PCR tests for SARS-CoV-2 were positive in both cases, and laboratory results showed microangiopathic haemolytic anaemia, thrombocytopenia, and acute kidney injury. No known aetiology for TMA was found in either case. Stool tests for Shigatoxin-producing Escherichia coli were negative. Coagulation tests, ADAMTS13 activity, serum complement levels, and homocysteine levels were all within the normal range. No known genetic mutation was found, including mutations of complement, diacylglycerol kinase epsilon, and cobalamin C. In the first case, eculizumab was administered due to persistent haemolysis and prolonged anuria. In conclusion, TMA may be associated with COVID-19 infection. Treatment with eculizumab may be beneficial in selected patients because of the potential activation of the complement system.
Topics: Male; Female; Humans; Infant; Child, Preschool; COVID-19; SARS-CoV-2; Thrombotic Microangiopathies; Purpura, Thrombotic Thrombocytopenic; Acute Kidney Injury
PubMed: 37485596
DOI: 10.1111/nep.14225 -
Nature Communications Jan 2024How cells coordinate cell cycling with cell survival and death remains incompletely understood. Here, we show that cell cycle arrest has a potent suppressive effect on...
How cells coordinate cell cycling with cell survival and death remains incompletely understood. Here, we show that cell cycle arrest has a potent suppressive effect on ferroptosis, a form of regulated cell death induced by overwhelming lipid peroxidation at cellular membranes. Mechanistically, cell cycle arrest induces diacylglycerol acyltransferase (DGAT)-dependent lipid droplet formation to sequester excessive polyunsaturated fatty acids (PUFAs) that accumulate in arrested cells in triacylglycerols (TAGs), resulting in ferroptosis suppression. Consequently, DGAT inhibition orchestrates a reshuffling of PUFAs from TAGs to phospholipids and re-sensitizes arrested cells to ferroptosis. We show that some slow-cycling antimitotic drug-resistant cancer cells, such as 5-fluorouracil-resistant cells, have accumulation of lipid droplets and that combined treatment with ferroptosis inducers and DGAT inhibitors effectively suppresses the growth of 5-fluorouracil-resistant tumors by inducing ferroptosis. Together, these results reveal a role for cell cycle arrest in driving ferroptosis resistance and suggest a ferroptosis-inducing therapeutic strategy to target slow-cycling therapy-resistant cancers.
Topics: Humans; Lipid Droplets; Ferroptosis; Fatty Acids, Unsaturated; Lipid Peroxidation; Triglycerides; Cell Cycle Checkpoints; Neoplasms; Diacylglycerol O-Acyltransferase; Fluorouracil
PubMed: 38167301
DOI: 10.1038/s41467-023-44412-7