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Upregulated hepatic lipogenesis from dietary sugars in response to low palmitate feeding supplies brain palmitate
The origin of brain palmitic acid (PAM) has been debated. Here, by using natural abundance carbon isotope ratios and RNA sequencing the authors show that the majority of brain PAM is maintained by hepatic PAM synthesis from dietary sugars during development and is upregulated in mice fed low PAM.
- Mackenzie E. Smith
- , Chuck T. Chen
- & Richard P. Bazinet
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| Open Access
Suppression of angiopoietin-like 4 reprograms endothelial cell metabolism and inhibits angiogenesis
Chaube et al. show that ANGPTL4 is an important player for endothelial cell metabolic function, impacting vascular permeability and angiogenesis. Knocking down ANGPTL4 increases fatty acid utilization but impairs glucose use, reducing neovascularization
- Balkrishna Chaube
- , Kathryn M. Citrin
- & Yajaira Suárez
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| Open Access
A conserved membrane protein negatively regulates Mce1 complexes in mycobacteria
Mycobacterial Mce systems are putative ABC transporters for lipids. Here, the authors revealed two distinct Mce1 complexes comprising different heterohexameric substrate binding assemblies that are negatively regulated via a novel mechanism.
- Yushu Chen
- , Yuchun Wang
- & Shu-Sin Chng
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| Open Access
Membrane manipulation by free fatty acids improves microbial plant polyphenol synthesis
The inherent toxicity of the aromatic compounds to the chassis strain hampers further improvement of bioproduction. Here, the authors show that membrane rigidifying effect of resveratrol can be attenuated by exogenous supplementation of palmitelaidic acid or linoleic acid in fermentation of Corynebacterium glutamicum.
- Apilaasha Tharmasothirajan
- , Josef Melcr
- & Jan Marienhagen
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| Open Access
Hepatic SREBP signaling requires SPRING to govern systemic lipid metabolism in mice and humans
Hendrix et al show that absence of hepatic Spring dramatically lowers levels of lipids in the liver and plasma in mice, and protects from development of diet-induced steatosis. In line, genetic variation in SPRING is associated with lipid levels in humans.
- Sebastian Hendrix
- , Jenina Kingma
- & Noam Zelcer
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| Open Access
Circulating trans fatty acids are associated with prostate cancer in Ghanaian and American men
Analyses of the association between fatty acids and prostate cancer have often neglected African patients. Here, the authors analyse 24 circulating fatty acids in Ghanaian, African American, and European American men, and explore the associations with socio-demographic factors, diet, FADS1/2 locus, and prostate cancer.
- Tsion Zewdu Minas
- , Brittany D. Lord
- & Stefan Ambs
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| Open Access
Endothelial cell CD36 regulates membrane ceramide formation, exosome fatty acid transfer and circulating fatty acid levels
Endothelial cell CD36 controls tissue fatty acid uptake. Here the authors show how fatty acid uptake by endothelial cells involves regulation of membrane ceramide production, caveolae dynamics, and exosome generation, these events facilitate transfer of circulating fatty acids to tissues and communication between endothelium and parenchyma.
- V. S. Peche
- , T. A. Pietka
- & N. A. Abumrad
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| Open Access
Ozone-enabled fatty acid discovery reveals unexpected diversity in the human lipidome
Fatty acids are fundamental biomolecular building blocks that are characterized by extraordinary structural diversity and present a formidable analytical challenge. Here the authors introduce a discovery workflow for de novo identification that adds more than 100 fatty acids to the human lipidome.
- Jan Philipp Menzel
- , Reuben S. E. Young
- & Stephen J. Blanksby
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Article
| Open Access
An engineered variant of MECR reductase reveals indispensability of long-chain acyl-ACPs for mitochondrial respiration
Mitochondrial fatty acid synthesis (mtFAS) generates the precursor for lipoic acid synthesis, but the role of longer fatty acid products has remained unclear. Here, the authors generated an engineered variant of human 2E-enoyl-ACP reductase (MECR) of mtFAS to study the role of long chain fatty acids.
- M. Tanvir Rahman
- , M. Kristian Koski
- & Kaija J. Autio
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| Open Access
Long-term statins administration exacerbates diabetic nephropathy via ectopic fat deposition in diabetic mice
Huang et al. investigated the effects of long-term statins administration in a mouse model for diabetes and found that it can worsen insulin resistance, renal inflammation and fibrosis. Statins increased renal lipid uptake and inhibited fatty acid oxidation, contributing to diabetic nephropathy.
- Tong-sheng Huang
- , Teng Wu
- & Wei-bin Cai
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| Open Access
Chronic intake of high dietary sucrose induces sexually dimorphic metabolic adaptations in mouse liver and adipose tissue
Dietary sugar intake may contribute to the development non-alcoholic fatty liver disease. Here the authors investigated the effects of chronic dietary sucrose on the liver-adipose-microbiome axis in mice, and report that sex is a moderating factor that influences sucrose-driven lipid storage in the liver and adipose tissue lipolysis.
- Erin J. Stephenson
- , Amanda S. Stayton
- & Joan C. Han
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| Open Access
Lipolysis regulates major transcriptional programs in brown adipocytes
β-Adrenergic signaling is a core regulator of brown adipocyte function. Here, the authors provide unbiased insight into the transcriptional network controlled by lipolysis in brown adipocytes, showing that lipolysis is required for much of the thermogenic gene program activated by β-adrenergic signals.
- Lasse K. Markussen
- , Elizabeth A. Rondini
- & Susanne Mandrup
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| Open Access
A negative-solvatochromic fluorescent probe for visualizing intracellular distributions of fatty acid metabolites
Metabolic distribution of fatty acids to organelles is an essential biological process for energy homeostasis. Here the authors report a fluorescent probe that allows multicolour visualisation of the intracellular distribution of exogenous fatty acids, metabolically incorporated as lipid components.
- Keiji Kajiwara
- , Hiroshi Osaki
- & Masayasu Taki
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| Open Access
Comparative metabolomics with Metaboseek reveals functions of a conserved fat metabolism pathway in C. elegans
Untargeted mass spectrometry-based metabolomics can reveal new biochemistry, but data analysis is challenging. Here, the authors develop Metaboseek, an open-source software that facilitates metabolite discovery, and apply it to characterize fatty acid alpha-oxidation in C. elegans.
- Maximilian J. Helf
- , Bennett W. Fox
- & Frank C. Schroeder
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| Open Access
Patched regulates lipid homeostasis by controlling cellular cholesterol levels
Cellular cholesterol levels are tightly regulated. Here, the authors show that the hedgehog signalling receptor PTCH is a cholesterol transporter. Reduction in PTCH activity leads to cellular cholesterol accumulation, changes in nuclear hormone receptor activity and fatty acid metabolism.
- Carla E. Cadena del Castillo
- , J. Thomas Hannich
- & Anne Spang
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| Open Access
Particulate organic matter as a functional soil component for persistent soil organic carbon
The fate of soil carbon is controlled by plant inputs, microbial activity, and the soil matrix. Here the authors extend the notion of plant-derived particulate organic matter, from an easily available and labile carbon substrate, to a functional component at which persistence of soil carbon is determined.
- Kristina Witzgall
- , Alix Vidal
- & Carsten W. Mueller
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| Open Access
Thioesterase superfamily member 1 undergoes stimulus-coupled conformational reorganization to regulate metabolism in mice
Cold exposure activates thermogenesis and fatty acid oxidation in brown fat, a process suppressed by Them1. Here, the authors show that cold induces Them1 phosphorylation and loss of puncta that suppress fatty acid use, leading to a diffuse localization and increased energy expenditure in mice.
- Yue Li
- , Norihiro Imai
- & Susan J. Hagen
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Article
| Open Access
Adipocyte PHLPP2 inhibition prevents obesity-induced fatty liver
Obesity can be associated with an increased risk of metabolic complications. Here, the authors show that adipocyte-specific ablation of the phosphatase PHLPP2 improves glucose homeostasis in high-fat diet fed obese mice, and that this may be due at least in part to PHLPP2 dephosphorylation of HSL.
- KyeongJin Kim
- , Jin Ku Kang
- & Utpal B. Pajvani
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| Open Access
Pattern recognition based on machine learning identifies oil adulteration and edible oil mixtures
Fraudulent adulteration of edible oils is based on the fact that their characteristic fatty acid profile can be mimicked with mixtures of other oil types. Here, the authors use a deep learning method to uncover fatty acid patterns discriminative for ten different plant oil types and to discern composition of mixtures.
- Kevin Lim
- , Kun Pan
- & Rong Hui Xiao
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| Open Access
CD36 facilitates fatty acid uptake by dynamic palmitoylation-regulated endocytosis
The mechanistic details of fatty acid uptake into cells remains poorly understood. Here, the authors identify CD36 internalization via cavaeolae and demonstrate dynamic palmitoylationof CD36 is required for endocytic uptake of fatty acids.
- Jian-Wei Hao
- , Juan Wang
- & Tong-Jin Zhao
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| Open Access
A dietary fatty acid counteracts neuronal mechanical sensitization
PIEZO2 is a critical component of the mechanism by which innocuous touch causes pain (tactile allodynia). Here, authors find that the dietary fatty acid margaric acid decreases PIEZO2 function in a dose-dependent manner and counteracts neuronal mechanical sensitization by a proalgesic agent.
- Luis O. Romero
- , Rebeca Caires
- & Valeria Vásquez
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| Open Access
Gating mechanism of elongating β-ketoacyl-ACP synthases
The formation of C-C bonds in fatty acid and polyketide biosynthesis depends on β-ketoacyl-acyl carrier protein (ACP) synthases (KSs). Here, the authors present structures of E.coli KSs bound to substrate mimetic bearing ACPs, providing insights into the catalytic mechanism underlying C-C bond forming reactions.
- Jeffrey T. Mindrebo
- , Ashay Patel
- & Michael D. Burkart
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| Open Access
Alterations in promoter interaction landscape and transcriptional network underlying metabolic adaptation to diet
Metabolic adaptation to different diets results in changes to gene expression. Here, the authors characterise the chromatin landscape and transcriptional network in mice on a diet of high saturated fat, compared to a diet high in carbohydrate, finding a dramatic reprogramming of the liver transcriptional network.
- Yufeng Qin
- , Sara A. Grimm
- & Paul A. Wade
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| Open Access
Dietary fatty acids promote lipid droplet diversity through seipin enrichment in an ER subdomain
Lipid droplets (LDs) are fat storage organelles that are initiated and expanded by seipins at ER contact sites. Here the authors show that the C. elegans seipin ortholog SEIP-1 is recruited to these sites by certain dietary fatty acids to support the expansion of a subset of LDs.
- Zhe Cao
- , Yan Hao
- & Ho Yi Mak
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| Open Access
Brain leptin reduces liver lipids by increasing hepatic triglyceride secretion and lowering lipogenesis
Obesity is associated with leptin resistance and rising blood leptin levels while central leptin exposure may be limited. Here, the authors show that brain leptin infusion reduces hepatic lipid content in rats by increasing hepatic VLDL secretion and lowering liver de novo lipogenesis via a vagal mechanism.
- Martina Theresa Hackl
- , Clemens Fürnsinn
- & Thomas Scherer
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Article
| Open Access
Dietary fatty acids fine-tune Piezo1 mechanical response
Piezo channels are mechanosensitive and rely on membrane composition to transduce physical stimuli into electrical signals. Here authors analyse the membrane components that modulate Piezo1 function using lipid profiling which shows that fatty acid metabolism can modulate ion channel activity.
- Luis O. Romero
- , Andrew E. Massey
- & Valeria Vásquez
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| Open Access
Dietary stearic acid regulates mitochondria in vivo in humans
Dietary fatty acids have different effects on human health. Here, the authors show that ingestion of the fatty acid C18:0, but not of C16:0, rapidly leads to fusion of mitochondria and fatty acid oxidation in humans, possibly explaining the health benefits of C18:0.
- Deniz Senyilmaz-Tiebe
- , Daniel H. Pfaff
- & Aurelio A. Teleman
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| Open Access
Insulin/Snail1 axis ameliorates fatty liver disease by epigenetically suppressing lipogenesis
Insulin promotes lipogenesis but, on the other hand, insulin resistance is associated with increased lipogenesis in the liver. Here the authors show that Snail1 is upregulated by insulin and inhibits lipogenesis by repressing Fasn expression but insulin-mediated Snail1 upregulation is impaired during obesity and insulin resistance.
- Yan Liu
- , Lin Jiang
- & Liangyou Rui
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| Open Access
Two distinct domains contribute to the substrate acyl chain length selectivity of plant acyl-ACP thioesterase
The substrate specificity of acyl-ACP thioesterase (TE) plays a crucial role in determining the product profile of type II fatty acid synthase. Utilizing two FatB-type acyl-ACP TEs, the authors here define determinants of substrate specificity and create synthetic enzymes with distinct catalytic traits.
- Fuyuan Jing
- , Le Zhao
- & Basil J. Nikolau
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Article
| Open Access
Short-chain fatty acids regulate systemic bone mass and protect from pathological bone loss
Short-chain fatty acids (SCFA) are a main class of metabolites derived from fermentation of dietary fibre in the intestine. Here, the authors show that dietary administration of SCFA is associated with inhibition of osteoclast differentiation, increased bone mass, and reduced pathological bone loss in mice.
- Sébastien Lucas
- , Yasunori Omata
- & Mario M. Zaiss
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| Open Access
HDAC3 is a molecular brake of the metabolic switch supporting white adipose tissue browning
Histone deacetylases, such as HDAC3, have been shown to alter cellular metabolism in various tissues. Here the authors show that HDAC3 regulates WAT metabolism by activating a futile cycle of fatty acid synthesis and oxidation, which supports WAT browning.
- Alessandra Ferrari
- , Raffaella Longo
- & Maurizio Crestani
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| Open Access
Pharmacological inhibition of adipose triglyceride lipase corrects high-fat diet-induced insulin resistance and hepatosteatosis in mice
The enzyme Atgl participates in the breakdown of lipids in adipose tissue. Here the authors show that pharmacological inhibition of Atgl reduces weight gain and improves metabolic health in mice fed a high-fat diet, without causing adverse effects in cardiac muscle associated with genetic depletion ofAtgl.
- Martina Schweiger
- , Matthias Romauch
- & Rudolf Zechner
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| Open Access
PNPLA1 is a transacylase essential for the generation of the skin barrier lipid ω-O-acylceramide
Loss-of-function mutations in an enzyme of unknown function, PNPLA1, cause dry and scaling skin in humans. Here Ohnoet al. show that PNPLA1 is a transacylase that acts in the final step of acylceramide production- esterification between ω-hydroxyceramide and linoleic acid acylceramide, yielding a lipid essential for skin barrier function.
- Yusuke Ohno
- , Nozomi Kamiyama
- & Akio Kihara
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| Open Access
Saturated palmitic acid induces myocardial inflammatory injuries through direct binding to TLR4 accessory protein MD2
The free fatty acid-mediated inflammatory activities are regulated through TLR4. Here the authors show that palmitic acid binds to MD2, initiating complex formation with TLR4, recruitment of MyD88, and subsequent activation of pro-inflammatory molecules, and that MD2 blockade protects against diet-induced cardiac dysfunction.
- Yi Wang
- , Yuanyuan Qian
- & Guang Liang
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| Open Access
The lipid sensor GPR120 promotes brown fat activation and FGF21 release from adipocytes
GPR120 is a G-protein-coupled receptor that binds polyunsaturated fatty acids. Here, the authors show that GPR120 is upregulated in brown fat in cold-exposed mice, and mediates thermogenic activation of brown fat via a mechanism that, at least in part, depends on the release of the adipokine FGF21.
- Tania Quesada-López
- , Rubén Cereijo
- & Francesc Villarroya
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Identification of the phytosphingosine metabolic pathway leading to odd-numbered fatty acids
Most cellular fatty acids contain even-numbered chains, and the origin of the small fraction of odd-numbered fatty acids remains unclear. Kondo et al.show that odd-numbered fatty acids are generated by metabolism of the long-chain base phytosphingosine in yeast and mammalian cells.
- Natsuki Kondo
- , Yusuke Ohno
- & Akio Kihara
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Insights into mitochondrial fatty acid synthesis from the structure of heterotetrameric 3-ketoacyl-ACP reductase/3R-hydroxyacyl-CoA dehydrogenase
3-Ketoacyl-ACP reductase is required for mitochondrial fatty acid synthesis. Venkatesan et al.present structures of this enzyme, show that the β-subunit is involved in fatty acid synthesis and propose a role for the α-subunit in routing unsaturated fatty acids into β-oxidation.
- Rajaram Venkatesan
- , Shiv K. Sah-Teli
- & Zhijun Chen
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De novo lipogenesis in human fat and liver is linked to ChREBP-β and metabolic health
Changes in the biosynthesis of fatty acids can influence tissue insulin sensitivity and the development of metabolic diseases. Eissing and colleagues show that de novolipogenesis in liver and adipose tissue is linked to metabolic health in humans and can be modulated by bariatric surgery.
- Leah Eissing
- , Thomas Scherer
- & Ludger Scheja
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Modular optimization of multi-gene pathways for fatty acids production in E. coli
Microbial fatty acid-derived fuels represent promising alternatives to the traditionally used fossil fuels. Koffas and colleagues report that E. colicentral metabolism can be modified to produce large quantities of fatty acids through a modular pathway engineering strategy.
- Peng Xu
- , Qin Gu
- & Mattheos A.G. Koffas
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The convergent evolution of defensive polyacetylenic fatty acid biosynthesis genes in soldier beetles
Soldier beetles use a polyacetylenic fatty acid to repel avian predators and protect their eggs. Haritoset al. find that three genes in soldier beetles convert oleic acid to a precursor of 8Z-dihydromatricaria acid—the first eukaryotic genes reported to produce conjugated polyacetylenic fatty acids.
- Victoria S. Haritos
- , Irene Horne
- & Mats Hamberg
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Article
| Open Access
Endocannabinoid-Goα signalling inhibits axon regeneration in Caenorhabditis elegans by antagonizing Gqα-PKC-JNK signalling
Axon regeneration inC. elegansis positively regulated by the JNK/MAP kinase pathway. Pastuhov and colleagues identify the endocannabinoid anandamide as a negative regulator of this pathway and show that anandamide inhibits axon regeneration in mature neurons after axotomy.
- Strahil Iv. Pastuhov
- , Kota Fujiki
- & Naoki Hisamoto
Evolutionarily related host and microbial pathways regulate fat desaturation in C. elegans