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Liver ACOX1 regulates levels of circulating lipids that promote metabolic health through adipose remodeling
The peroxisomal β-oxidation enzyme ACOX1 increases in liver with obesity, but the physiological significance is unclear. Here, the authors show that liver-specific knockout of Acox1 leads to accumulation of omega-3 VLCFAs that promote metabolic health through activation of GPR120 in adipose tissue.
- Dongliang Lu
- , Anyuan He
- & Irfan J. Lodhi
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Article
| Open Access
Lipopolysaccharide binding protein resists hepatic oxidative stress by regulating lipid droplet homeostasis
Oxidative stress triggers lipid accumulation in cells by sequestering triglycerides in lipid droplets. Here, the authors show that lipopolysaccharide-binding protein interacts with redox sensor PRDX4 to control lipid-redox balance and promotes triglyceride accumulation in droplets by capturing unsaturated lipids.
- Qilun Zhang
- , Xuting Shen
- & Haoshu Fang
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Article
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LDL receptor-related protein 5 selectively transports unesterified polyunsaturated fatty acids to intracellular compartments
The mechanisms transporting fatty acids into the cell are not completely understood. Here, the authors discover a selective transporter for a specific class of lipids, and show its role in regulating neutrophil function during myocardial ischemia-reperfusion injury.
- Wenwen Tang
- , Yi Luan
- & Dianqing Wu
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Article
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A fast-acting lipid checkpoint in G1 prevents mitotic defects
Lipid synthesis increases during the cell cycle to ensure sufficient membrane mass. Here, authors identify a lipid checkpoint in G1 phase that prevents cells from starting the cell cycle if lipid synthesis is low, thereby preventing mitotic defects.
- Marielle S. Köberlin
- , Yilin Fan
- & Tobias Meyer
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Article
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Structures of human prostaglandin F2α receptor reveal the mechanism of ligand and G protein selectivity
Cryo-EM structures reveal the molecular mechanism of ligands and G protein selectivity for prostaglandin F2α receptor, providing guidance for development of better postpartum hemorrhage drugs.
- Xiuqing Lv
- , Kaixuan Gao
- & Xiangyu Liu
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Palmitoyltransferase DHHC9 and acyl protein thioesterase APT1 modulate renal fibrosis through regulating β-catenin palmitoylation
The role and mechanisms for protein palmitoylation in renal fibrosis remain unclear. Here, the authors show that DHHC9 and APT1 catalysed β-catenin S-palmitoylation on Cys300 contributes to renal fibrosis, which may provide a new therapeutic strategy for chronic kidney diseases.
- Mengru Gu
- , Hanlu Jiang
- & Chunsun Dai
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Article
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Cytoplasmic Endonuclease G promotes nonalcoholic fatty liver disease via mTORC2-AKT-ACLY and endoplasmic reticulum stress
Endonuclease G is known to translocate to the nucleus during apoptosis, but less is known about its role in the cytosol. Here, the authors show that cytoplasmic endonuclease G activates mTORC2 signaling and ER stress to promote NAFLD in female mice.
- Wenjun Wang
- , Junyang Tan
- & Qinghua Zhou
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Regulation of cellular cholesterol distribution via non-vesicular lipid transport at ER-Golgi contact sites
The molecular mechanisms responsible for cellular cholesterol distribution remain unclear. Here, the authors identify a key role of lipid transfer proteins ORP9, OSBP, and GRAMD1s in maintaining cholesterol levels in the Golgi and plasma membrane.
- Tomoki Naito
- , Haoning Yang
- & Yasunori Saheki
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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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Sphingosine 1-phosphate mediates adiponectin receptor signaling essential for lipid homeostasis and embryogenesis
Cells and organisms requires proper membrane composition, which the cell must modulate as membrane lipids are primary acquired from the diet. Here, Ruiz et al. identify a conserved pathway connecting the fluidity regulators AdipoR1/2 with fatty acid desaturase SCD to mediate membrane homeostasis.
- Mario Ruiz
- , Ranjan Devkota
- & Marc Pilon
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Article
| Open Access
Hepatocyte phosphatase DUSP22 mitigates NASH-HCC progression by targeting FAK
Mechanisms underlying the pathogenesis of nonalcoholic steatohepatitis are unclear. Here, the authors show that ROS-mediated DUSP22 degradation participates in the progression of fatty liver, contributing to the development of NASH and associated HCC via regulating FAK and its downstream ERK1/2 and NF-κB signaling cascade.
- Chenxu Ge
- , Jun Tan
- & Minxuan Xu
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Article
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An acquired phosphatidylinositol 4-phosphate transport initiates T-cell deterioration and leukemogenesis
The oxysterol-binding protein-related protein 4 (ORP4L) is expressed in T-cell acute lymphoblastic leukemia and is required for leukemogenesis. Here the authors show that ORP4L orchestrates the transport of the phospholipid PI(4)P from Golgi to the plasma membrane, contributing to PI3K/AKT hyperactivation and T-cell leukemogenesis.
- Wenbin Zhong
- , Weize Lin
- & Daoguang Yan
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Article
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Adipocyte lysoplasmalogenase TMEM86A regulates plasmalogen homeostasis and protein kinase A-dependent energy metabolism
Dysregulation of plasmalogen metabolism in adipose tissue is associated with metabolic diseases. Here the authors characterize the role of adipocyte TMEM86A as a lysoplasmalogenase and show its deletion is protective against high fat diet induced metabolic disease, an effect that can be recapitulated by plasmenyl lysophosphatidylethanolamine 18:0 supplementation.
- Yoon Keun Cho
- , Young Cheol Yoon
- & Yun-Hee Lee
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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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Differential activation mechanisms of lipid GPCRs by lysophosphatidic acid and sphingosine 1-phosphate
Liu et al. report structures of human sphingosine 1-phosphate (S1P) receptor 1 (S1P1) in complex with Gi and S1P or the multiple sclerosis (MS) drug Siponimod, as well as human lysophosphatidic acid (LPA) receptor 1 (LPA1) in complex with Gi and LPA, revealing distinct conformations of the lysophospholipids interacting with their cognate GPCRs.
- Shian Liu
- , Navid Paknejad
- & Xin-Yun Huang
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Article
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Perilipin 5 links mitochondrial uncoupled respiration in brown fat to healthy white fat remodeling and systemic glucose tolerance
Perilipin 5 is a lipid droplet protein that interacts with PGC1α in the nucleus to regulate mitochondrial metabolism. Here the authors use genetically engineered mouse models to determine the physiologic role of Perilipin 5, and show that it regulates mitochondrial adaptations to cold, as well as systemic energy metabolism.
- Violeta I. Gallardo-Montejano
- , Chaofeng Yang
- & Perry E. Bickel
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Article
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Inositol triphosphate-triggered calcium release blocks lipid exchange at endoplasmic reticulum-Golgi contact sites
The interplay between non-vesicular lipid transport, calcium signaling, and membrane dynamics is unclear. Here, the authors report a function for inositol triphosphate hydrolysis by the inositol 5-phosphatase INPP5A in controlling lipid exchange at interorganelle membrane contact sites between the endoplasmic reticulum and Golgi.
- Mouhannad Malek
- , Anna M. Wawrzyniak
- & Volker Haucke
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Polyunsaturated fatty acids and p38-MAPK link metabolic reprogramming to cytoprotective gene expression during dietary restriction
Metabolic reprogramming during Dietary Restriction (DR) activates cytoprotective gene expression. Here the authors show that PUFAs generated during DR signal via the p38-MAPK pathway to enhance cytoprotective gene expression, contributing to increased longevity.
- Manish Chamoli
- , Anita Goyala
- & Arnab Mukhopadhyay
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Rab35-regulated lipid turnover by myotubularins represses mTORC1 activity and controls myelin growth
Charcot-Marie-Tooth (CMT) is an inherited peripheral neuropathy. Here, the authors show that Rab35 forms a complex with genes implicated in CMT, MTMR13 and MTMR2, which regulates myelin growth by controlling mTORC1 signaling through lipid turnover.
- Linda Sawade
- , Federica Grandi
- & Volker Haucke
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Cell metabolism regulates integrin mechanosensing via an SLC3A2-dependent sphingolipid biosynthesis pathway
Mechanical and metabolic cues contribute to regulate cell and tissue homeostasis but how they are integrated is not known. Here the authors show that the amino acid transporter and integrin coreceptor CD98hc regulates mechanical signaling downstream of integrins indirectly through regulating sphingolipid availability.
- Etienne Boulter
- , Soline Estrach
- & Chloé C. Féral
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A phosphatidylinositol 4,5-bisphosphate redistribution-based sensing mechanism initiates a phagocytosis programing
The origin of Fc receptor-based phagocytosis is unknown, although plasma lipid redistribution after solid structure binding induces similar phagocytic signaling. Here, Mu et al. show that PIP2 accumulation from plasma membrane deformation recruits Moesin to trigger receptor-independent phagocytosis.
- Libing Mu
- , Zhongyuan Tu
- & Yan Shi
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| Open Access
C16-ceramide is a natural regulatory ligand of p53 in cellular stress response
Ceramides are important participants of signal transduction, regulating fundamental cellular processes. Here authors show that C16-ceramide binds to the tumor suppressor p53, disrupts its interaction with MDM2 and facilitates p53 accumulation and activation of its downstream targets.
- Baharan Fekry
- , Kristen A. Jeffries
- & Natalia I. Krupenko
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Genetic and pharmacological regulation of the endocannabinoid CB1 receptor in Duchenne muscular dystrophy
The regenerative capacity of muscle stem cells is impaired in Duchenne muscular dystrophy (DMD). Here, the authors show that the endocannabinoid receptor CB1 is activated by PAX7 in muscle stem cells, and that pharmacological inhibition of CB1 promotes stem cell activation and ameliorates symptoms in DMD mouse models.
- Fabio A. Iannotti
- , Ester Pagano
- & Vincenzo Di Marzo
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The structure of iPLA2β reveals dimeric active sites and suggests mechanisms of regulation and localization
Calcium-independent phospholipase A2β (iPLA2β) is involved in many physiological and pathological processes but the underlying mechanisms are largely unknown. Here, the authors present the structure of dimeric iPLA2β, providing insights into the regulation of its activity and cellular localization.
- Konstantin R. Malley
- , Olga Koroleva
- & Sergey Korolev
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Macrophage VLDLR mediates obesity-induced insulin resistance with adipose tissue inflammation
VLDLR regulates cellular lipoprotein uptake and storage. Here, the authors show that VLDLR, expressed on adipose tissue macrophages, is upregulated in obesity and promotes adipose tissue inflammation by upregulating ceramide production and facilitating M1-like macrophage polarization.
- Kyung Cheul Shin
- , Injae Hwang
- & Jae Bum Kim
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Article
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ORP5 and ORP8 bind phosphatidylinositol-4, 5-biphosphate (PtdIns(4,5)P
2) and regulate its level at the plasma membrane
ORP5/8 are endoplasmic reticulum (ER) membrane proteins implicated in lipid trafficking that localize to ER-plasma membrane (PM) contacts and maintain membrane homeostasis. Here the authors show that PtdIns(4,5)P 2 plays a critical role in the targeting and function of ORP5/8 at the PM.
- Rajesh Ghai
- , Ximing Du
- & Hongyuan Yang
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Article
| Open Access
Membrane-binding and activation of LKB1 by phosphatidic acid is essential for development and tumour suppression
LKB1 regulates various cellular processes such as cell proliferation, energy homeostasis and cell polarity and is frequently downregulated in various tumours. Here the authors show that LKB1 activation requires direct binding to phospholipids and show this has an implication for carcinogenesis.
- Giada Dogliotti
- , Lars Kullmann
- & Michael P. Krahn
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Article
| Open Access
HS1BP3 negatively regulates autophagy by modulation of phosphatidic acid levels
Autophagy must be tightly controlled at each step of the process. Here the authors show that HS1BP3 binds phosphatidic acid (PA) at autophagosome precursors and negatively regulates autophagosome formation by modulating the activity and localization of the PA-producing enzyme phospholipase D1.
- Petter Holland
- , Helene Knævelsrud
- & Anne Simonsen
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Kinetic disruption of lipid rafts is a mechanosensor for phospholipase D
Mechanosensation by biological membranes can be relayed by mechanical tension to ion channels. Here the authors show that phospholipase D (PLD) is activated by mechanical disruption of lipid rafts which allows PLD to mix with its substrate in the lipid membrane, and propose a kinetic model of force transduction.
- E. Nicholas Petersen
- , Hae-Won Chung
- & Scott B. Hansen
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Article
| Open Access
Genome-wide RNAi screen reveals ALK1 mediates LDL uptake and transcytosis in endothelial cells
Atherosclerosis is caused by low-density lipoprotein (LDL) buildup in the vessel wall, a process thought to be mediated by LDL receptor alone. Here, the authors show that the endothelium can uptake LDL via ALK1, a TGFβ signalling receptor, suggesting new therapies for blocking LDL accumulation in the vessel wall.
- Jan R. Kraehling
- , John H. Chidlow
- & William C. Sessa
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Article
| Open Access
ORP4L is essential for T-cell acute lymphoblastic leukemia cell survival
Lymphocytic leukaemia cells are characterized by high respiratory rates. Here, the authors report that the oxysterol-binding protein ORPL4 sustains mitochondrial respiration in T-cell acute lymphoblastic leukaemia cells by regulating Ca2+release from the endoplasmic reticulum.
- Wenbin Zhong
- , Qing Yi
- & Daoguang Yan
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Article
| Open Access
Sphingosine-1-phosphate promotes erythrocyte glycolysis and oxygen release for adaptation to high-altitude hypoxia
The presence of the signalling lipid Sphingosine 1-phosphate (S1P) in erythrocytes has unclear physiological implications. Here the authors show that the S1P-generating enzyme Sphingosine kinase type 1 and its product S1P play an important role in the red blood cell adaptation to hypoxic environments in mice and humans.
- Kaiqi Sun
- , Yujin Zhang
- & Yang Xia
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Article
| Open Access
Septin 9 induces lipid droplets growth by a phosphatidylinositol-5-phosphate and microtubule-dependent mechanism hijacked by HCV
The accumulation of lipid droplets is often observed in hepatitis C virus infection, but the mechanism of their formation is not known. Here the authors show that septin 9 expression is increased in infected livers, and a septin 9/phosphatidylinositol 5-phosphate signalling pathway regulates the growth of lipid droplets.
- Abdellah Akil
- , Juan Peng
- & Ama Gassama-Diagne
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Article
| Open Access
Soluble LR11/SorLA represses thermogenesis in adipose tissue and correlates with BMI in humans
Brown adipose tissue (BAT) thermogenesis is an important determinant of organismal energy expenditure in mammals. Here, Whittle et al. report that the protein sLR11 is a negative regulator of BAT activity in mice, repressing thermogenesis by inhibiting BMP/Smad signalling in brown adipocytes.
- Andrew J. Whittle
- , Meizi Jiang
- & Hideaki Bujo
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Tamoxifen augments the innate immune function of neutrophils through modulation of intracellular ceramide
Tamoxifen, widely used to modulate oestrogen receptor activity in breast cancer treatment, also regulates sphingolipid metabolism. Here the authors show that the latter activity of tamoxifen stimulates pro-inflammatory and antibacterial activities of human neutrophils.
- Ross Corriden
- , Andrew Hollands
- & Victor Nizet
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Article
| Open Access
AMPK activation promotes lipid droplet dispersion on detyrosinated microtubules to increase mitochondrial fatty acid oxidation
Lipid droplets (LDs) supply fatty acids to cellular processes and move bidirectionally on microtubules. Here the authors show that nutrient starvation causes dispersal of mitochondria and LD to the periphery of the cell along detyrosinated microtubules and increases LD–mitochondria interactions in an AMPK-dependent manner.
- Albert Herms
- , Marta Bosch
- & Albert Pol
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Article
| Open Access
Photoswitchable fatty acids enable optical control of TRPV1
Fatty acids are ancient lipids with numerous functions, from metabolic processes as a source of energy to structural and signalling roles within cell membranes. Here, the authors present azobenzene-modified fatty acids and their application as photoswitchable agonists of the Vanilloid Receptor 1.
- James Allen Frank
- , Mirko Moroni
- & Dirk Trauner
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Article
| Open Access
A muscle-liver-fat signalling axis is essential for central control of adaptive adipose remodelling
Skeletal muscle proteolysis can affect organismal energy homeostasis. Here, the authors provide molecular insight into this process by showing that muscle-derived alanine acts as a signal that triggers FGF21 secretion from the liver, which then regulates lipolysis and browning of white fat tissue.
- Noriaki Shimizu
- , Takako Maruyama
- & Hirotoshi Tanaka
Post-resolution macrophages shape long-term tissue immunity and integrity in a mouse model of pneumococcal pneumonia