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| Open AccessTreatment of skeletal and non-skeletal alterations of Mucopolysaccharidosis type IVA by AAV-mediated gene therapy
Mucopolysaccharidosis type IVA (MPSIVA) is a lysosomal storage disorder causing severe skeletal and non-skeletal alterations in patients. Here, the authors generate a MPSIVA rat model that mimics the disabling human pathology and develop an AAV9-Galns gene therapy to treat the disease.
- Joan Bertolin
- , Víctor Sánchez
- & Fatima Bosch
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Article
| Open AccessLoss of SNORA73 reprograms cellular metabolism and protects against steatohepatitis
Lipid induced stress contributes to metabolic diseases. Here the authors identify small nucleolar RNA 73 (SNORA73) in a screen for genes that protect against lipotoxicity and show that deficiency of SNORA73 reprograms oxidative metabolism and protects against steatohepatitis in mice.
- Arthur C. Sletten
- , Jessica W. Davidson
- & Jean E. Schaffer
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Article
| Open AccessTargeting of eIF6-driven translation induces a metabolic rewiring that reduces NAFLD and the consequent evolution to hepatocellular carcinoma
Lipid accumulation in the liver leads to nonalcoholic fatty liver disease (NAFLD) that is a risk factor for developing hepatocellular carcinoma (HCC). Here, the authors show that activation of the translation initiation factor eIF6 promotes lipid accumulation in the liver and targeting eIF6 in murine models reduces NAFLD and associated HCC.
- Alessandra Scagliola
- , Annarita Miluzio
- & Stefano Biffo
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| Open AccessA small molecule that induces translational readthrough of CFTR nonsense mutations by eRF1 depletion
Premature termination codons can cause early translation termination and lead to disease. Here the authors perform a screen to identify compounds with readthrough activity and show that these reduce eRF1 levels to suppress premature termination associated with cystic fibrosis.
- Jyoti Sharma
- , Ming Du
- & David M. Bedwell
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Article
| Open AccessVisceral obesity and insulin resistance associate with CD36 deletion in lymphatic endothelial cells
Genetic variants in CD36 have been associated with metabolic syndrome. Here, the authors found that lymphatic vessel integrity and lipid transport are influenced by CD36 expression, and lymphatic endothelial cell CD36 deficiency causes visceral obesity and insulin resistance, which are risk factors for metabolic syndrome and diabetes.
- Vincenza Cifarelli
- , Sila Appak-Baskoy
- & Nada A. Abumrad
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Article
| Open AccessA neural basis for brain leptin action on reducing type 1 diabetic hyperglycemia
Leptin can rescue hyperglycemia in type 1 diabetes, but the underlying mechanisms for this effect are not clear. Here, the authors report that leptin action is mediated by inhibition of the heightened activity of arcuate GABA neurons in murine models of type 1 diabetes through restoring nutrient sensing.
- Shengjie Fan
- , Yuanzhong Xu
- & Qingchun Tong
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Article
| Open AccessExploiting pyocyanin to treat mitochondrial disease due to respiratory complex III dysfunction
Mitochondrial diseases, including those caused by defects in complex III of the respiratory chain, lack curative treatments. Here the authors report that the small molecule pyocyanin has beneficial effects in cells derived from patients with complex III-deficiency as well as in fly and zebrafish genetic models with reduced complex III activity.
- Roberta Peruzzo
- , Samantha Corrà
- & Ildikò Szabò
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| Open AccessThe Pah-R261Q mouse reveals oxidative stress associated with amyloid-like hepatic aggregation of mutant phenylalanine hydroxylase
Phenylketonuria (PKU) is caused by autosomal recessive variants in phenylalanine hydroxylase (PAH) and can lead to neurotoxicity. Here the authors describe a mouse model of PKU based on a mutation in phenylalanine hydroxylase (R261Q) which replicates traits of this disease and shows a proteostasis defect and oxidative stress, implying a gain-of-function contribution to the disease phenotype.
- Oscar Aubi
- , Karina S. Prestegård
- & Aurora Martinez
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| Open AccessFasting alters the gut microbiome reducing blood pressure and body weight in metabolic syndrome patients
Nutritional modification including fasting has been shown to reduce cardiometabolic risk linked to western diet. Here the authors show implementation of fasting resulted in alterations to the intestinal microbiota, and circulating immune cells, improving blood pressure and body weight in patients with metabolic syndrome.
- András Maifeld
- , Hendrik Bartolomaeus
- & Sofia K. Forslund
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Article
| Open AccessLentivirus-mediated gene therapy for Fabry disease
Treatments for Fabry disease, an inherited lysosomal disorder caused by the deficiency of the enzyme alpha-galactosidase A, are not fully efficacious. Here the authors report a single-arm phase I trial of gene therapy with autologous, lentivirus-transduced, hematopoietic cells that express alpha-galactosidase A to demonstrate that this approach is safe in five patients with Fabry disease.
- Aneal Khan
- , Dwayne L. Barber
- & Jeffrey A. Medin
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Article
| Open AccessmicroRNA-33 maintains adaptive thermogenesis via enhanced sympathetic nerve activity
Adaptive thermogenesis is regulated by central neuronal circuits. Here, the authors show that microRNA-33 in the brain contributes to the maintenance of brown adipose tissue thermogenesis and whole-body energy balance via enhanced sympathetic nerve tone, and regulating the expression of GABAa receptor subunits.
- Takahiro Horie
- , Tetsushi Nakao
- & Koh Ono
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Article
| Open AccessRare genetic variants affecting urine metabolite levels link population variation to inborn errors of metabolism
Metabolites are indicators of health and disease; genetic studies can reveal variants influencing their levels. Here, the authors investigate the contribution of rare, exonic variants on the levels of urine metabolites and generate predictions on metabolic consequences underlying metabolic disease.
- Yurong Cheng
- , Pascal Schlosser
- & Anna Köttgen
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Article
| Open AccessAn integrative multiomic network model links lipid metabolism to glucose regulation in coronary artery disease
Some cholesterol-lowering drugs can increase the risk of type 2 diabetes, but the mechanism behind this is not fully understood. Here the authors show that there is a single genetic regulatory module that influences both cholesterol levels and glucose levels, providing a link between cholesterol levels and diabetes.
- Ariella T. Cohain
- , William T. Barrington
- & Eric E. Schadt
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Article
| Open AccessCytosolic sequestration of the vitamin D receptor as a therapeutic option for vitamin D-induced hypercalcemia
Current therapeutic strategies for vitamin D-induced hypercalcemia are poorly efficient. Here the authors identify a new interaction between the vitamin D receptor (VDR) and WBP4 controlling the subcellular localization of VDR and show that ZK168281, a VDR antagonist, enhances the interaction between VDR and WBP4 blunting VDR signalling and normalizing calcium levels in vitamin D-intoxicated mice.
- Daniela Rovito
- , Anna Y. Belorusova
- & Daniel Metzger
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| Open AccessAstrocytic pyruvate dehydrogenase kinase-2 is involved in hypothalamic inflammation in mouse models of diabetes
Hypothalamic inflammation is involved in the pathogenesis of diabetes. The underlying mechanisms are unclear. Here, the authors show that astrocytic PDK2 ablation or inhibition attenuates hypothalamic inflammation in mouse models of diabetes.
- Md Habibur Rahman
- , Anup Bhusal
- & Kyoungho Suk
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Article
| Open AccessDual mRNA therapy restores metabolic function in long-term studies in mice with propionic acidemia
Propionic acidemia is a serious pediatric inherited disorder with no effective treatments. Here the authors demonstrate that delivering dual mRNAs as an enzyme replacement approach can be used as an effective therapy in a mouse model of propionic acidemia, with potential applicability to chronically administer multiple mRNAs in other genetic disorders.
- Lei Jiang
- , Ji-Sun Park
- & Lin T. Guey
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Article
| Open AccessAberrant methylation underlies insulin gene expression in human insulinoma
Insulinomas are rare, benign beta cell tumours which overproduce insulin and have been associated to epigenetic alterations. Here the authors characterise insulinoma methylomes, finding changes in promoter methylation and chromatin structure proposed to drive the pathological expression of insulin.
- Esra Karakose
- , Huan Wang
- & Luca Lambertini
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Article
| Open AccessAdaptive thermogenesis enhances the life-threatening response to heat in mice with an Ryr1 mutation
Individuals with malignant hyperthermia susceptibility (MHS) suffer from lifethreatening responses to heat. Here the authors demonstrate that adaptive thermogenesis from brown adipose tissue contributes to this heat sensitivity in a preclinical mouse model of MHS
- Hui J. Wang
- , Chang Seok Lee
- & Susan L. Hamilton
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| Open AccessTime-restricted feeding alters lipid and amino acid metabolite rhythmicity without perturbing clock gene expression
Time restricted feeding has several health benefits. Here the authors perform a randomised cross-over study with 11 men with overweight/obesity to investigate how time restricted feeding affects skeletal muscle and serum, and report that it does not affect the core circadian machinery, but modifies periodicity in amino acid related metabolites and transporters.
- Leonidas S. Lundell
- , Evelyn B. Parr
- & John A. Hawley
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| Open AccessGut microbial co-abundance networks show specificity in inflammatory bowel disease and obesity
Gut microbiome alterations have been linked to inflammatory bowel disease (IBD) and obesity. Here, the authors characterize the metagenomes of four large human cohorts and perform co-abundance network analysis showing that dysbiosis in disease is marked by the altered co-abundance relationships, suggesting that pathway coabundance networks are more heterogeneous than species network.
- Lianmin Chen
- , Valerie Collij
- & Jingyuan Fu
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Article
| Open AccessParaventricular hypothalamus mediates diurnal rhythm of metabolism
Defective rhythmic metabolism is associated with high-fat diet feeding and obesity. The authors show that the clock gene BMAL1 drives paraventricular hypothalamic neuron activity via rhythmic GABAergic neurotransmission, and that this mediates diurnal metabolism and diet-induced obesity.
- Eun Ran Kim
- , Yuanzhong Xu
- & Qingchun Tong
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| Open AccessAdipocyte Piezo1 mediates obesogenic adipogenesis through the FGF1/FGFR1 signaling pathway in mice
Adipose tissue expansion occurs via enlargement of adipocytes as well as the generation of new fat cells, the latter being associated with more favorable metabolic outcomes. Here, the authors show that activation of adipocyte Piezo1 results in release of FGF1 and stimulates the differentiation of adipocyte precursor cells.
- ShengPeng Wang
- , Shuang Cao
- & Stefan Offermanns
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Article
| Open AccessThe scaffold protein p62 regulates adaptive thermogenesis through ATF2 nuclear target activation
Beta-adrenergic stimulation of brown adipose tissue leads to thermogenesis via the activating transcription factor 2 (ATF2) mediated expression of the thermogenic genes Ucp1 and Pgc-1α. Here, the authors show that the scaffold protein p62 regulates brown adipose tissue function through modifying ATF2 genomic binding and subsequent Ucp1 and Pgc-1α induction.
- Katrin Fischer
- , Anna Fenzl
- & Timo D. Müller
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Article
| Open AccessHepatic TET3 contributes to type-2 diabetes by inducing the HNF4α fetal isoform
The HNF4α gene contains two promoters, which are thought to be active in the fetal and adult liver, the latter contributing to hepatic glucose production. Here the authors show that the fetal isoform of HNF4a is induced in mouse livers upon fasting and in type-2 diabetes in a manner regulated by TET3.
- Da Li
- , Tiefeng Cao
- & Yingqun Huang
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Article
| Open AccessA spontaneous mitonuclear epistasis converging on Rieske Fe-S protein exacerbates complex III deficiency in mice
A difference in the survival of respiratory chain complex III deficient Bcs1lp.S78G mice was observed between two congenic mouse strains. Here the authors show how in one of the strains the combined effects of a spontaneously arising non-pathogenic variant and the disease-causing Bcs1lp.S78G mutation exacerbate CIII deficiency and disease progression.
- Janne Purhonen
- , Vladislav Grigorjev
- & Jukka Kallijärvi
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Article
| Open AccessInactivation of NF-κB2 (p52) restrains hepatic glucagon response via preserving PDE4B induction
Elevated glucagon level in obesity and diabetes promotes hepatic glucose production and hyperglycemia. Here the authors report that NF-κB2 augments the hepatic glucagon responses by inhibiting PDE4B induction, and that metformin lowers blood glucose in part by inhibiting NF-κB2.
- Wen-Song Zhang
- , An Pan
- & Ping Li
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Article
| Open AccessAdipose HuR protects against diet-induced obesity and insulin resistance
Human antigen R (HuR) is a RNA-binding protein. Here the authors investigate its role in adipose tissue and find that it protects mice from diet-induced obesity, prevents adipocyte hypertrophy, and promotes lipolysis, which may at least in part be due to HuR-dependent ATGL mRNA stability regulation demonstrated in-vitro.
- Jingyuan Li
- , Li Gong
- & Wencheng Zhang
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| Open AccessCostimulation of type-2 innate lymphoid cells by GITR promotes effector function and ameliorates type 2 diabetes
Type-2 innate lymphoid cells (ILC2s) are an immune population secreting Th2 cytokines playing a role in the regulation of adipose metabolic homeostasis. Here the authors show that engagement of GITR, a member of the TNF superfamily, in activated ILC2s is protective against insulin resistance in both a preventive and a therapeutic manner in the context of obesity.
- Lauriane Galle-Treger
- , Ishwarya Sankaranarayanan
- & Omid Akbari
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Article
| Open AccessCRISPR/Cas9-mediated glycolate oxidase disruption is an efficacious and safe treatment for primary hyperoxaluria type I
Substrate reduction therapies (SRT) are a promising therapeutic approach for monogenic inherited metabolic diseases. Here the authors evaluate the therapeutic potential of an in vivo CRISPR/Cas9-mediated SRT to treat primary hyperoxaluria type I and demonstrate its safety and efficacy.
- Nerea Zabaleta
- , Miren Barberia
- & Juan R. Rodriguez-Madoz
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| Open AccessDownregulation of macrophage Irs2 by hyperinsulinemia impairs IL-4-indeuced M2a-subtype macrophage activation in obesity
Obesity is associated with low-grade chronic inflammation. Here the authors show that the activation of anti-inflammatory M2a-subtype macrophages requires the IL4/Irs2/Akt pathway. Due to decreased Irs2 expression this pathway is impaired in obese mice thus leading to a defect in M2a activation.
- Tetsuya Kubota
- , Mariko Inoue
- & Takashi Kadowaki
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Article
| Open AccessProteome-wide analysis of USP14 substrates revealed its role in hepatosteatosis via stabilization of FASN
Ubiquitin-specific protease 14 (USP14) is a proteasome-associated deubiquitinating enzyme with known roles in physiology and disease. Here the authors show that fatty acid synthase (FASN) is a substrate of USP14, and that by stabilizing FASN, it plays a role in hepatosteatosis.
- Bin Liu
- , Shangwen Jiang
- & Minjia Tan
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| Open AccessCoordinated targeting of cold and nicotinic receptors synergistically improves obesity and type 2 diabetes
Tobacco smoking and cold exposure are environmental modulators of human energy metabolism suppressing appetite and increasing energy expenditure, respectively. Here, the authors develop a novel pharmacological strategy in which they simultaneously mimic the metabolic benefits of both phenomena through small-molecule combination therapy, and show that this treatment improves metabolic health of obese mice.
- Christoffer Clemmensen
- , Sigrid Jall
- & Matthias H. Tschöp
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| Open AccessArgininosuccinic aciduria fosters neuronal nitrosative stress reversed by Asl gene transfer
Patients with mutations in the ASL gene present with argininosuccinic aciduria characterised by hyperammonaemia and cognitive impairment. Here, the authors show that cerebral disease involves neuronal nitrosative/oxidative stress that is not induced by hyperammonaemia, and that it can be reversed using AAV-ASL directed to liver and brain in mice.
- Julien Baruteau
- , Dany P. Perocheau
- & Simon N. Waddington
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Article
| Open AccessStructural basis for the activation of acid ceramidase
Acid ceramidase (aCDase) hydrolyzes lysosomal membrane ceramide into sphingosine and its dysfunction leads to a variety of disease phenotypes. Here, the authors present structures of aCDase in its proenzyme and autocleaved forms, which provides insight into its mechanism of action.
- Ahmad Gebai
- , Alexei Gorelik
- & Bhushan Nagar
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Article
| Open AccessCDK6 inhibits white to beige fat transition by suppressing RUNX1
Beige adipocytes can arise from transdifferentiation of mature white adipocytes. Here the authors identify CDK6 as a key molecule involved in the white-to-beige adipocyte transdifferentiation and, therefore, as a regulator of organismal energy homeostasis in mice.
- Xiaoli Hou
- , Yongzhao Zhang
- & Miaofen G. Hu
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| Open AccessDe novo adipocyte differentiation from Pdgfrβ+ preadipocytes protects against pathologic visceral adipose expansion in obesity
Adipocyte hyperplasia is thought to have beneficial metabolic effects in obesity, but definitive evidence is lacking. Here, Shao et al. promote de novo formation of adipocytes in visceral white adipose tissue (WAT) of adult mice through inducible overexpression of Pparg in Pdgfrβ+ preadipocytes and show that this protects from pathological WAT remodeling.
- Mengle Shao
- , Lavanya Vishvanath
- & Rana K. Gupta
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Article
| Open AccessHarnessing insulin- and leptin-induced oxidation of PTP1B for therapeutic development
The activity of protein tyrosine phosphatase PTP1B, a major metabolic regulator, depends on its oxidation state. Here the authors identify and characterize a small molecule that targets the oxidized, inactive form of PTP1B, suggesting a new therapeutic approach to diabetes and obesity.
- Navasona Krishnan
- , Christopher A. Bonham
- & Nicholas K. Tonks
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Article
| Open AccessHepatic Crtc2 controls whole body energy metabolism via a miR-34a-Fgf21 axis
CREB-regulated transcription coactivator 2, CRTC2, has been associated with regulation of glucose and lipid homeostasis. Here Han et al. show that Creb/Crtc2 modulates lipid and glucose metabolism by inhibiting the expression of mi-R34 that, in turn, represses the expression of Sirt1 and PPARα and consequently Fgf21 levels.
- Hye-Sook Han
- , Byeong Hun Choi
- & Seung-Hoi Koo
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Article
| Open AccessHDX reveals the conformational dynamics of DNA sequence specific VDR co-activator interactions
The vitamin D receptor/retinoid X receptor-α heterodimer (VDRRXRα) regulates bone mineralization. Here the authors employ hydrogen/deuterium exchange (HDX) mass spectrometry to study the conformational dynamics of VDRRXRα and give mechanistic insights into how VDRRXRα controls the transcriptional activity of specific genes.
- Jie Zheng
- , Mi Ra Chang
- & Patrick R. Griffin
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Article
| Open AccessActivating de novo mutations in NFE2L2 encoding NRF2 cause a multisystem disorder
The NRF2 transcription factor regulates the response to stress in mammalian cells. Here, the authors show that activating mutations in NRF2, commonly found in cancer cells, are found in four patients with a multisystem disorder characterized by immunodeficiency and neurological symptoms.
- Peter Huppke
- , Susann Weissbach
- & Jutta Gärtner
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Article
| Open AccessInsights into Hunter syndrome from the structure of iduronate-2-sulfatase
Hunter syndrome is a lysosomal storage disease caused by mutations in the enzyme iduronate-2-sulfatase (IDS). Here, the authors present the IDS crystal structure and give mechanistic insights into mutations that cause Hunter syndrome.
- Mykhaylo Demydchuk
- , Chris H. Hill
- & Randy J. Read
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Article
| Open AccessPharmacological 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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Article
| Open AccessSulfheme formation during homocysteine S-oxygenation by catalase in cancers and neurodegenerative diseases
High levels of homocysteine in cells are linked to pathological states. Here, the authors report that homocysteine inactivates catalase by modifying the heme group, impairing cellular redox homeostasis, and show that this modification occurs in cancer cells and in a cellular model of Parkinson’s disease.
- Dominique Padovani
- , Assia Hessani
- & Isabelle Artaud
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Article
| Open AccessDisposal of iron by a mutant form of lipocalin 2
Iron overload can be either hereditary or acquired via transfusions, and current treatments include the use of iron chelators that have adverse effects in some patients. Here the authors modify siderocalin to enhance iron excretion in urine, and demonstrate therapeutic efficacy in iron overload mouse models.
- Jonathan Barasch
- , Maria Hollmen
- & Andong Qiu
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Article
| Open AccessHepatocyte TRAF3 promotes liver steatosis and systemic insulin resistance through targeting TAK1-dependent signalling
TRAF family proteins regulate immune signalling cascades. Here, the authors show that TRAF3 is upregulated in the liver in non-alcoholic fatty liver disease, promoting insulin resistance, inflammation and hepatic steatosis via its interaction with the kinase TAK1.
- Pi-Xiao Wang
- , Xiao-Jing Zhang
- & Hongliang Li
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Article
| Open AccessChronic acidosis in the tumour microenvironment selects for overexpression of LAMP2 in the plasma membrane
The protein LAMP2 functions to protect lysosomal membranes from acid proteolysis. In this study, the authors show that malignant cells adapt to the acidic tumour microenvironment by redirecting LAMP2 from lysosomes to the plasma membrane.
- Mehdi Damaghi
- , Narges K. Tafreshi
- & Robert J Gillies
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Article
| Open AccessClass III PI3K regulates organismal glucose homeostasis by providing negative feedback on hepatic insulin signalling
PI3K is activated as a result of insulin receptor (IR) signalling. Here the authors show that activation of specific class III PI3Ks in response to insulin promotes IR endocytosis and lysosomal degradation, providing negative feedback on IR signalling by reducing the time IR is activated.
- Ivan Nemazanyy
- , Guillaume Montagnac
- & Ganna Panasyuk
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Article
| Open AccesseIF6 coordinates insulin sensitivity and lipid metabolism by coupling translation to transcription
Insulin enhances mRNA translation via the translation initiation factor eIF6. Here, Brina et al. show that insulin-mediated activation of eIF6 is associated with the selective translation of genes involved in glycolysis and lipid synthesis with characteristic G/C-rich and uORF sequences in their mRNA.
- Daniela Brina
- , Annarita Miluzio
- & Stefano Biffo
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Article |
Adiponectin regulates psoriasiform skin inflammation by suppressing IL-17 production from γδ-T cells
Adiponectin levels are decreased in metabolic syndrome and psoriasis patients. Here the authors show that adiponectin suppresses the pathogenic production of IL-17 of γδ T cells, and adiponectin administration improves psoriasis-like symptoms in a mouse model of the disease.
- Sayaka Shibata
- , Yayoi Tada
- & Shinichi Sato