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| Open AccessLipopolysaccharide 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
| Open AccessIn-depth correlation analysis between tear glucose and blood glucose using a wireless smart contact lens
The correlation between tear glucose and blood glucose is still controversial. Here, the authors demonstrated the correlation between tear glucose and blood glucose in both animal models and human subjects using smart contact lenses.
- Wonjung Park
- , Hunkyu Seo
- & Jang-Ung Park
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Article
| Open AccessTrimethylamine N-oxide impairs β-cell function and glucose tolerance
β-Cell dysfunction is a hallmark of type 2 diabetes. Here, the authors show that trimethylamine N-oxide (TMAO (a microbiota metabolite)) induces β-cell dysfunction and type 2 diabetes in mice through NLRP3 inflammasome activation and calcium transients.
- Lijuan Kong
- , Qijin Zhao
- & Pingping Li
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Article
| Open AccessPla2g12b drives expansion of triglyceride-rich lipoproteins
Thierer and colleagues identify PLA2G12B as a key gene driving triglyceride incorporation into lipoproteins and show that disruption of this activity provides protection from atherosclerosis.
- James H. Thierer
- , Ombretta Foresti
- & Steven A. Farber
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Article
| Open AccessGlucocorticoids increase adiposity by stimulating Krüppel-like factor 9 expression in macrophages
Glucocorticoids, potent anti-inflammatory drugs, can cause or exacerbate obesity, yet the underlying molecular mechanisms remain largely unknown. Here, the authors show KLF9 in macrophages integrates the beneficial anti-inflammatory and adverse metabolic effects of glucocorticoids.
- Yinliang Zhang
- , Chunyuan Du
- & Yongsheng Chang
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Article
| Open AccessTransport mechanism of human bilirubin transporter ABCC2 tuned by the inter-module regulatory domain
Human ABC transporter ABCC2 transports conjugated bilirubin from hepatocyte to bile duct, dysfunction of which causes Dubin-Johnson syndrome. Here, the authors provide structural insights into the substrate specificity of ABCC2 and the transport mechanism regulated by the R domain.
- Yao-Xu Mao
- , Zhi-Peng Chen
- & Yuxing Chen
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Article
| Open AccessLeukemia inhibitory factor suppresses hepatic de novo lipogenesis and induces cachexia in mice
Cancer cachexia is a systemic syndrome characterized by dramatic weight loss and decline in adipose tissue and skeletal muscle mass. Here, the authors show that overexpression of leukemia inhibitory factor (LIF), a secreted cytokine, suppresses de novo lipogenesis and induces cachexia in mice.
- Xue Yang
- , Jianming Wang
- & Wenwei Hu
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Article
| Open AccessA naturally occurring polyacetylene isolated from carrots promotes health and delays signatures of aging
Ameliorating or preventing signatures of aging in humans using natural compounds is an exciting area of research. Here the authors isolate a previously unknown phytochemical from carrots which activates defence mechanisms against oxidative stress and extends lifespan in worms, and improves glucose metabolism, promotes exercise capacity, and protects from frailty at higher age in mice.
- Carolin Thomas
- , Reto Erni
- & Michael Ristow
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Article
| Open AccessShuttle peptide delivers base editor RNPs to rhesus monkey airway epithelial cells in vivo
Gene editing strategies for cystic fibrosis are challenging. Here the authors improve on their previously reported shuttle peptide noncovalently combined with Cas ribonucleoprotein (RNP), and derive the S315 peptide for delivery: they show base editing in the respiratory tract of the rhesus macaques.
- Katarina Kulhankova
- , Soumba Traore
- & Paul B. McCray Jr.
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Article
| Open AccessFructose overconsumption impairs hepatic manganese homeostasis and ammonia disposal
Manganese is an essential trace element for the activity of arginase in the process of urea generation and ammonia disposal in the liver. Here, the authors show that fructose overconsumption impairs hepatic Mn homeostasis and ammonia disposal in male mice.
- Jian-Hui Shi
- , Yu-Xia Chen
- & Weiping J. Zhang
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Article
| Open AccessMutual modulation of gut microbiota and the immune system in type 1 diabetes models
Type-1 diabetes pathogenesis has been strongly linked with changes in the intestinal microbiota. Here, the authors demonstrate that mice susceptible to type-1 diabetes become resistant when co-housed with resistant mice, an effect that was associated with changes in gut microbiota, gut permeability, and the immune system.
- Estela Rosell-Mases
- , Alba Santiago
- & Chaysavanh Manichanh
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Article
| Open AccessSLC35D3 promotes white adipose tissue browning to ameliorate obesity by NOTCH signaling
White adipose tissue is closely associated with energy expenditure and obesity. Here, the authors show that SLC35D3 promotes white adipose tissue browning through the NOTCH1 signalling pathway and SLC35D3 may be a potential therapeutic target for obesity and related complications.
- Hongrui Wang
- , Liang Yu
- & Yibo Wang
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Article
| Open AccessIntegrating human activity into food environments can better predict cardiometabolic diseases in the United States
Previous studies on the connection between food environments and cardiometabolic diseases have yielded inconclusive results. Here, the authors show that integrating human activity into assessments of food environments can better predict the prevalence of cardiometabolic diseases.
- Ran Xu
- , Xiao Huang
- & Xiang Chen
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Article
| Open AccessTranscriptional repression of beige fat innervation via a YAP/TAZ-S100B axis
Sympathetic innervation is essential for the development of functional beige fat that maintains metabolic homeostasis. Qiu and colleagues discover that YAP/TAZ can act as a brake on the beige fat innervation by blocking PRDM16-C/EBPβ-mediated S100b expression.
- Xun Huang
- , Xinmeng Li
- & Yifu Qiu
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Article
| Open AccessFollicle-stimulating hormone orchestrates glucose-stimulated insulin secretion of pancreatic islets
Follicle-stimulating hormone (FSH) is involved in mammalian reproduction, but several studies have suggested a role of FSH and its receptor in extragonadal tissue. Here, the authors show that FSH orchestrates glucose-stimulated insulin secretion (GSIS) via its receptor on pancreatic β-cells, with pre-menopausal FSH levels dose-dependently promoting GSIS and postmenopausal FSH levels inhibiting this effect.
- Yi Cheng
- , Hong Zhu
- & He-Feng Huang
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Article
| Open AccessBile acids-mediated intracellular cholesterol transport promotes intestinal cholesterol absorption and NPC1L1 recycling
Intestinal cholesterol is taken into endocytic recycling compartment via NPC1L1-mediated endocytosis. Here the authors show that certain bile acids facilitate cholesterol transport to the endoplasmic reticulum from endocytic recycling compartment in cells and NPC1L1 is then recycled back to the plasma membrane.
- Jian Xiao
- , Le-Wei Dong
- & Bao-Liang Song
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Article
| Open AccessMetabolic phenotyping of BMI to characterize cardiometabolic risk: evidence from large population-based cohorts
A substantial proportion of patients with cardiometabolic conditions appear to have normal BMI. Conversely, not all obese individuals exhibit these disorders. Here, we show that a metabolic BMI score derived from lipidomic models, allows quantify metabolic dysregulation in obesity independently of BMI.
- Habtamu B. Beyene
- , Corey Giles
- & Peter J. Meikle
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Article
| Open AccessCytoplasmic 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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Article
| Open AccessGlycerol 3-phosphate phosphatase/PGPH-2 counters metabolic stress and promotes healthy aging via a glycogen sensing-AMPK-HLH-30-autophagy axis in C. elegans
Activation of the glycerol shunt mimics calorie restriction, protects from glucotoxicity, and promotes healthy aging. Here, Possik et al. uncover the underlying mechanism and identify the AMPK-TFEB autophagy pathway as critical to the healthy aging phenotype.
- Elite Possik
- , Laura-Lee Klein
- & Marc Prentki
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Article
| Open AccessInhibition of AXL receptor tyrosine kinase enhances brown adipose tissue functionality in mice
Brown adipose tissue is a promising target for the treatment of obesity with the potential to increase energy expenditure. Here, the authors use pharmacological and genetic approaches to block AXL receptor activation and show that its inhibition enhances brown adipocyte functionality and thermogenesis, leading to weight loss and metabolic improvements in mice.
- Vissarion Efthymiou
- , Lianggong Ding
- & Christian Wolfrum
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Article
| Open AccessThe structural pathology for hypophosphatasia caused by malfunctional tissue non-specific alkaline phosphatase
Hypophosphatasia (HPP) is a bone disease caused by mutations in tissue non-specific alkaline phosphatase (TNAP). Here, authors solved the crystal and cryoEM structures of TNAP, shedding light on the molecular mechanisms underlying HPP.
- Yating Yu
- , Kewei Rong
- & An Qin
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Article
| Open AccessRapid and definitive treatment of phenylketonuria in variant-humanized mice with corrective editing
The PAH P281L variant is one of the most common variants identified in phenylketonuria (PKU) patients. Here, the authors use base editing, enabled by lipid nanoparticle/mRNA technology, to directly correct the P281L variant in the liver in PKU mice and definitively treat the disease within 2 days.
- Dominique L. Brooks
- , Manuel J. Carrasco
- & Xiao Wang
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Article
| Open AccessLigand dependent interaction between PC-TP and PPARδ mitigates diet-induced hepatic steatosis in male mice
Deletion of PC-TP has many beneficial effects, mostly ascribed to its role in regulating THEM2. Here, the authors show a novel interaction between PC-TP and PPARδ that explains aspects of the beneficial metabolic phenotype associated with PC-TP deletion.
- Samuel A. Druzak
- , Matteo Tardelli
- & Eric A. Ortlund
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Article
| Open AccessUDP-glucuronate metabolism controls RIPK1-driven liver damage in nonalcoholic steatohepatitis
The mechanism underlying hepatocytes apoptosis, a key process in the progression of nonalcoholic steatohepatitis, remains unclear. Here, the authors identify UGDH and its catalytic product UDP-glucuronate as suppressors of NASH-associated liver damage by inhibiting RIPK1- dependent hepatocyte apoptosis.
- Tao Zhang
- , Na Zhang
- & Jinyang Gu
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Article
| Open AccessTime-of-day defines NAD+ efficacy to treat diet-induced metabolic disease by synchronizing the hepatic clock in mice
The timing of NAD + supply determines its efficacy to treat metabolic disease. Here, the authors show that increasing NAD + at the early active phase maximizes weight loss and glucose regulation in mice. NAD + can displace the phase of the liver clock which can cause circadian misalignment.
- Quetzalcoatl Escalante-Covarrubias
- , Lucía Mendoza-Viveros
- & Lorena Aguilar-Arnal
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Article
| Open AccessLipid-droplet associated mitochondria promote fatty-acid oxidation through a distinct bioenergetic pattern in male Wistar rats
How the liver mitochondria seamlessly regulate lipogenesis and lipid oxidation is unknown. Here, the authors report two functionally distinct populations of mitochondria, cytoplasmic and lipid droplet-associated mitochondria, and demonstrate that the latter’s lipid oxidation function is impaired in a rat NAFLD model.
- Noble Kumar Talari
- , Ushodaya Mattam
- & Naresh Babu V. Sepuri
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Article
| Open AccessEstimation and implications of the genetic architecture of fasting and non-fasting blood glucose
Most genetic studies of glucose levels have been done on fasting samples, which can be difficult to obtain. Here, the authors identify 156 genetic loci controlling the physiological variation of glucose levels in healthy non-fasting individuals, demonstrating that the results non-fasting samples can be used to predict fasting glucose levels.
- Zhen Qiao
- , Julia Sidorenko
- & Loic Yengo
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Article
| Open AccessEffect of β2-agonist treatment on insulin-stimulated peripheral glucose disposal in healthy men in a randomised placebo-controlled trial
β2-agonist treatment improves skeletal muscle glucose uptake and whole-body glucose homeostasis in rodents. Here the authors report that two-weeks of treatment with the β2-agonist clenbuterol improves insulin-stimulated glucose disposal in healthy young men in a double-blinded, randomized cross-over trial.
- Sten M. M. van Beek
- , Yvonne M. H. Bruls
- & Joris Hoeks
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Article
| Open AccessPharmacological inhibition of Lin28 promotes ketogenesis and restores lipid homeostasis in models of non-alcoholic fatty liver disease
The Lin28/let-7 axis regulates metabolic pathways in normal and pathological contexts. Here the authors show that pharmacological inhibition of Lin28 protects against lipid accumulation in multiple preclinical models of nonalcoholic fatty liver disease.
- Evangelia Lekka
- , Aleksandra Kokanovic
- & Jonathan Hall
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Article
| Open AccessTargeting APLN/APJ restores blood-testis barrier and improves spermatogenesis in murine and human diabetic models
Type 2 diabetes often presents with reproductive disorders, including reduced male and female fertility. Here they show that diabetes disrupts the APLN signaling axis in the testes and that spermatogenesis can be restored through treatment with an APLN antagonist.
- Ke Song
- , Xinyan Yang
- & Xiao-Yang Zhao
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Article
| Open AccessSENP1 prevents steatohepatitis by suppressing RIPK1-driven apoptosis and inflammation
The receptor-interacting protein (RIPK1) promotes cell death and contributes to nonalcoholic steatohepatitis pathogenesis. Here the authors report that a SUMO-specific protease, SENP1, deSUMOylates RIPK1 and inhibits cell death in a mouse model of non-alcoholic fatty liver disease.
- Lingjie Yan
- , Tao Zhang
- & Daichao Xu
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Article
| Open AccessSpecialist multidisciplinary input maximises rare disease diagnoses from whole genome sequencing
Whole genome sequencing is emerging as a first-line test for rare genetic diseases. In this study, authors maximise diagnoses by supplementing existing semiautomated analyses with clinically driven reevaluation of genomic data by a specialist multidisciplinary team.
- William L. Macken
- , Micol Falabella
- & Robert D. S. Pitceathly
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Article
| Open AccessGCAF(TMEM251) regulates lysosome biogenesis by activating the mannose-6-phosphate pathway
Lysosomal biogenesis errors often result in diseases including mucolipidosis. Here Zhang and Yang et al. identify TMEM251/GCAF as a mannose-6-phosphate modification regulator that is necessary for correct lysosomal targeting, and classify Mucolipidosis Type V as resulting from GCAF mutations.
- Weichao Zhang
- , Xi Yang
- & Ming Li
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Article
| Open AccessIn vivo adenine base editing reverts C282Y and improves iron metabolism in hemochromatosis mice
Hemochromatosis is a metabolic disorder caused by mutations in the HFE gene. Here, the authors show that a single administration of AAV8 vectors expressing an Adenine Base Editor facilitates efficient in vivo gene correction in hepatocytes and leads to improvement of iron-specific parameters in the liver and the blood in mouse models of the disease.
- Alice Rovai
- , BoMee Chung
- & Michael Ott
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Article
| Open AccessIn vivo lentiviral vector gene therapy to cure hereditary tyrosinemia type 1 and prevent development of precancerous and cancerous lesions
Hereditary tyrosinemia type 1 (HT1) is an inborn error of metabolism caused by a deficiency in fumarylacetoacetate hydrolase (FAH). Here, the authors show in an animal model that HT1 can be treated via in vivo portal vein administration of a lentiviral vector carrying the human FAH transgene.
- Clara T. Nicolas
- , Caitlin J. VanLith
- & Joseph B. Lillegard
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Article
| Open AccessOral administration of Blautia wexlerae ameliorates obesity and type 2 diabetes via metabolic remodeling of the gut microbiota
Here, the authors inversely associate Blautia wexlerae with obesity and type 2 diabetes mellitus in humans and further show that administration of B. wexlerae to mice decrease both high-fat diet–induced obesity and diabetes via modulating gut microbial metabolism.
- Koji Hosomi
- , Mayu Saito
- & Jun Kunisawa
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Article
| Open AccessNeonatal gene therapy achieves sustained disease rescue of maple syrup urine disease in mice
Maple syrup urine disease (MSUD) is a rare inborn error of metabolism, which is currently treated with life-long low-protein diet that can be challenging to maintain. Here the authors develop an AAV8-directed gene therapy providing sustainable disease rescue in a mouse model of MSUD.
- Clément Pontoizeau
- , Marcelo Simon-Sola
- & Manuel Schiff
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Article
| Open AccessCa2+-mediated higher-order assembly of heterodimers in amino acid transport system b0,+ biogenesis and cystinuria
Cystinuria is caused by mutations in heterodimeric amino acid transporter known as system b0,+. Here, authors discover that Ca2+ stabilizes the interface between two system b0,+ regulatory subunits rBAT, leading to super-dimerization of the b0,+AT–rBAT heterodimer, facilitating system b0,+ maturation.
- Yongchan Lee
- , Pattama Wiriyasermkul
- & Shushi Nagamori
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Article
| Open AccessTherapeutic homology-independent targeted integration in retina and liver
Limits of AAV-mediated gene therapy include targeting dominant mutations and inducing long-term transgene expression. Here, the authors show that AAV-HITI results in efficient allele-independent integration of a donor DNA in both retina and liver providing therapeutic benefit in mouse models of either a genetic form of blindness or a lysosomal storage disease, respectively.
- Patrizia Tornabene
- , Rita Ferla
- & Alberto Auricchio
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Article
| Open AccessGut microbiota production of trimethyl-5-aminovaleric acid reduces fatty acid oxidation and accelerates cardiac hypertrophy
Intestinal microbiota alterations may affect heart function through the production of gut-derived metabolites. Here the authors found that gut microbiota-derived TMAVA is a key determinant for the development of cardiac hypertrophy through inhibition of carnitine synthesis and subsequent fatty acid oxidation.
- Mingming Zhao
- , Haoran Wei
- & Lemin Zheng
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Article
| Open AccessLysosomal Ca2+-mediated TFEB activation modulates mitophagy and functional adaptation of pancreatic β-cells to metabolic stress
Autophagy is important for pancreatic β-cell function, however, the role of mitophagy and mechanism for mitophagy in β-cells are unclear. Here the authors report that in stressed β-cells, lysosomal Ca2+ release promotes mitophagy via activation of the transcription factor EB (TFEB) and loss of β-cell TFEB aggravates glucose intolerance during high-fat diet.
- Kihyoun Park
- , Hyejin Lim
- & Myung-Shik Lee
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Article
| Open AccessDihydroceramide- and ceramide-profiling provides insights into human cardiometabolic disease etiology
Among lipid classes, ceramides are linked to impaired cardiometabolic health. Here the authors report the association of specific ceramides and dihydroceramides on the risk of developing type 2 diabetes and or cardiovascular disease in a prospective population cohort.
- C. Wittenbecher
- , R. Cuadrat
- & M. B. Schulze
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Article
| Open AccessA propolis-derived small molecule ameliorates metabolic syndrome in obese mice by targeting the CREB/CRTC2 transcriptional complex
Disruption of CREB/CRTC2, a key gluconeogenic transcriptional complex, has been shown to ameliorate insulin resistance in mice. Here, the authors show that the inhibitor artipllin C and the synthetic compound A57, which presents with higher inhibitory activity, improve insulin sensitivity in obese mice by inhibiting CREB-CRTC2 interaction.
- Yaqiong Chen
- , Jiang Wang
- & Yi Liu
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Article
| Open AccessClenbuterol exerts antidiabetic activity through metabolic reprogramming of skeletal muscle cells
In this study, the authors demonstrated that agents targeting skeletal muscle metabolism by modulating β2-adrenergic receptor-dependent signaling may prove beneficial as novel antidiabetic drugs.
- Jaroslawna Meister
- , Derek B. J. Bone
- & Jürgen Wess
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Article
| Open AccessDynamic regulation of N6,2′-O-dimethyladenosine (m6Am) in obesity
m6A and m6Am are two prevalent mRNA modifications which are target for removal by the fat mass and obesity gene FTO. Here the authors capture the differential profile of these two modifications in the liver of obese mice and identify dynamic translation regulation by the m6Am modification.
- Moshe Shay Ben-Haim
- , Yishay Pinto
- & Gideon Rechavi
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Article
| Open AccessSexual dimorphism in glucose metabolism is shaped by androgen-driven gut microbiome
Male sex is a risk factor for impaired glucose metabolism and type 2 diabetes. Here the authors identify that androgen modulates the gut microbiome, which drives insulin resistance and contributes to sexual dimorphism in glucose metabolism in mice.
- Aibo Gao
- , Junlei Su
- & Weiqing Wang
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Article
| Open AccessGP73 is a TBC-domain Rab GTPase-activating protein contributing to the pathogenesis of non-alcoholic fatty liver disease without obesity
Dysregulation of lipid metabolism and transport contribute to the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Here the authors identify GP73 as a TBC-domain Rab GTPase-activating protein that regulates very low-density lipoprotein export and promotes NAFLD development in mice.
- Yumeng Peng
- , Qiang Zeng
- & Congwen Wei
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Article
| Open AccessHepatic expression of GAA results in enhanced enzyme bioavailability in mice and non-human primates
Pompe disease is currently treated with enzyme replacement therapy (ERT) with recombinant human acid alpha-glucosidase (GAA). Here, the authors show hepatic-directed gene therapy with AAV vectors enhances GAA bioavailability compared with ERT, resulting in improved rescue of the disease phenotype in mice and broad enzyme distribution in mice and non-human primates.
- Helena Costa-Verdera
- , Fanny Collaud
- & Federico Mingozzi
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Article
| Open AccessThe transcriptional corepressor CtBP2 serves as a metabolite sensor orchestrating hepatic glucose and lipid homeostasis
Sensing of nutrient status coordinates the regulation of liver glucose and lipid metabolism, and is important for metabolic homeostasis. Here the authors report that transcriptional the corepressor CtBP2 can sense nutrient status and coordinate repression of liver glucose and lipid metabolism via Fox01 and SREBP1, respectively.
- Motohiro Sekiya
- , Kenta Kainoh
- & Hitoshi Shimano