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| Open AccessA metabolic associated fatty liver disease risk variant in MBOAT7 regulates toll like receptor induced outcomes
Hyperactivation of the toll-like receptors (TLRs) have been implicated as risk factors for more severe forms of disease in COVID-19 and metabolic (dysfunction) associated fatty liver disease (MAFLD). Here the authors report that MBOAT7 is reduced in macrophages of patients with MAFLD and COVID-19, and acts as a negative regulator of TLR signalling.
- Jawaher Alharthi
- , Ali Bayoumi
- & Mohammed Eslam
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Article
| Open AccessRestoring cellular magnesium balance through Cyclin M4 protects against acetaminophen-induced liver damage
Drug induced liver injury (DILI) is an important cause acute liver failure. Here the authors report that serum Mg2+ serum levels decrease in patients with DILI as well as in preclinical animal models treated with acetaminophen overdose, and that early intervention targeting the Mg2+ transporter Cyclin M4 may be beneficial for acetaminophen overdose in preclinical models.
- Irene González-Recio
- , Jorge Simón
- & Maria L Martínez-Chantar
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Article
| Open AccessReduced alcohol preference and intake after fecal transplant in patients with alcohol use disorder is transmissible to germ-free mice
Gut microbiota composition is altered in patients with alcohol use disorder, and fecal microbiota transplant reduced alcohol craving in patients with alcohol use disorder and liver cirrhosis in a phase 1 clinical trial. Here the authors used stool samples collected in the trial to report that this phenotype is transmissible via microbial transfer to germ free mice, as assessed by reduced ethanol acceptance, intake and preference.
- Jennifer T. Wolstenholme
- , Justin M. Saunders
- & Jasmohan S. Bajaj
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Article
| Open AccessHepatocyte 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
| Open AccessTFEB regulates sulfur amino acid and coenzyme A metabolism to support hepatic metabolic adaptation and redox homeostasis
Matye el al. show that coenzyme-A and glutathione deficiency in NAFLD limits fatty acid oxidation and antioxidant defence capacity. The nutrient sensing transcription factor EB induces autophagy–lysosome proteolysis and methionine cycle-transsulfuration to maintain hepatic cysteine, coenzyme-A and glutathione availability.
- David Matye
- , Sumedha Gunewardena
- & Tiangang Li
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Article
| Open AccessFunctional genomics uncovers the transcription factor BNC2 as required for myofibroblastic activation in fibrosis
Myofibroblasts contribute to the development of liver fibrosis. Here, the authors report that the transcription factor Basonuclin 2 (BNC2) integrates fibrogenic signals and drives myofibroblastic transcriptional activation in liver fibrosis.
- Marie Bobowski-Gerard
- , Clémence Boulet
- & Jérôme Eeckhoute
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Article
| Open AccessO-GlcNAcylation enhances CPS1 catalytic efficiency for ammonia and promotes ureagenesis
Hyperammonemia occurs in liver diseases affecting ureagenesis, and is life-threatening. Here, the authors show that liver UDP-GlcNAc is increased during hyperammonemia, leading to O-GlcNAcylation of the rate-limiting ureagenesis enzyme CPS1, that enhanced ureagenesis and ammonia detoxification. They also showed that pharmacological increase of protein O-GlcNAcylation reduces hyperammonemia in mouse models of liver disease.
- Leandro R. Soria
- , Georgios Makris
- & Nicola Brunetti-Pierri
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Article
| Open AccessNeutralization of hepatitis B virus with vaccine-escape mutations by hepatitis B vaccine with large-HBs antigen
The hepatitis B vaccine is recognised as the most effective approach in reducing hepatitis-B-related morbidity; vaccine-escape mutations are however capable of infecting vaccinated individuals. In this work, authors aim to establish a hepatitis B vaccine candidate, which they assess in rhesus macaques in terms of efficacy and safety.
- Ayaka Washizaki
- , Asako Murayama
- & Takanobu Kato
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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 AccessSpermidine-mediated hypusination of translation factor EIF5A improves mitochondrial fatty acid oxidation and prevents non-alcoholic steatohepatitis progression
Spermidine, a polyamine reported to extend lifespan and reduce the risk of age-related diseases, serves as a substrate for the post-translational modification hypusination. Here the authors report that EIF5A hypusination, which regulates mitochondrial protein synthesis, is reduced during non-alcoholic steatohepatitis (NASH), which can be prevented by spermidine to inhibit the progression of NASH in mice.
- Jin Zhou
- , Jeremy Pang
- & Paul Michael Yen
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Article
| Open AccessBiliary NIK promotes ductular reaction and liver injury and fibrosis in mice
Excessive expansion of cholangiocytes in the liver leads to ductular reaction and liver disease. Here, the authors show that genetic ablation, or pharmacological inhibition, of biliary NIK blocks ductular reaction, liver inflammation, and liver fibrosis in mice by modulating secretion of cholangiokines that mediate liver inflammation and fibrosis.
- Zhiguo Zhang
- , Xiao Zhong
- & Liangyou Rui
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Article
| Open AccessMettl3-mediated mRNA m6A modification controls postnatal liver development by modulating the transcription factor Hnf4a
m6A is the most abundant RNA modification of eukaryotic mRNAs and is involved in various physiological and pathological processes. Here the authors show a role for Mettl3-mediated RNA m6A modification in postnatal liver development by regulating the Hnf4a-centered transcriptional network
- Yan Xu
- , Zhuowei Zhou
- & Qi Zhang
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Article
| Open AccessDeficiency of WTAP in hepatocytes induces lipoatrophy and non-alcoholic steatohepatitis (NASH)
Ectopic lipid accumulation and inflammation are the essential signs of NASH. Here, the authors show that hepatic WTAP is a key integrative repressor of ectopic lipid accumulation and inflammation during NASH progression, and hepatic deletion of Wtap promotes both of them, leading to NASH
- Xinzhi Li
- , Kaixin Ding
- & Zheng Chen
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Article
| Open AccessLactational delivery of Triclosan promotes non-alcoholic fatty liver disease in newborn mice
Triclosan is an antimicrobial additive in consumer products that has been detected in human breast milk. Here the authors report that exposure of pregnant mice to triclosan leads to lactational exposure to newborns and the development of liver steatosis.
- André A. Weber
- , Xiaojing Yang
- & Robert H. Tukey
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Article
| Open AccessLoss of immunity-related GTPase GM4951 leads to nonalcoholic fatty liver disease without obesity
Obesity is a major risk factor for fatty liver disease. Here, using a forward genetic screen, the authors identify the gene GM4951 as a GTPase involved in lipid oxidation and development of NAFLD in mice.
- Zhao Zhang
- , Yu Xun
- & Bruce Beutler
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Article
| Open AccessImbalanced gut microbiota fuels hepatocellular carcinoma development by shaping the hepatic inflammatory microenvironment
Steatohepatitis is a chronic hepatic inflammation associated with increased risk of hepatocellular carcinoma progression. Here the authors show that intestinal dysbiosis in mice lacking the inflammasome sensor molecule NLRP6 aggravates steatohepatitis and accelerates liver cancer progression, a process that can be delayed by antibiotic treatment.
- Kai Markus Schneider
- , Antje Mohs
- & Christian Trautwein
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Article
| Open AccessInfluence of NAFLD and bariatric surgery on hepatic and adipose tissue mitochondrial biogenesis and respiration
Impaired mitochondrial function in liver tissue may contribute to the pathogenesis and disease progression of nonalcoholic fatty liver disease (NAFLD). Here the authors report that patients with obesity have lower mitochondrial capacity in adipose tissues but higher capacity in the liver, without overall associations to NAFLD severity, and that bariatric surgery increases hepatic mitochondrial respiration and mitochondrial biogenesis.
- Julie S. Pedersen
- , Marte O. Rygg
- & Flemming Dela
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Article
| Open AccessAutophagy impairment in liver CD11c+ cells promotes non-alcoholic fatty liver disease through production of IL-23
The function of autophagy and how this affects non-alcoholic fatty liver disease is not fully known. Here the authors show that in mice with a targeted disruption of the autophagy pathway in CD11c+ cells, development of NAFLD is accelerated involving IL-23 and blocking of IL-23 reduces disease.
- Lauriane Galle-Treger
- , Doumet Georges Helou
- & Omid Akbari
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Article
| Open AccessCharacterisation and induction of tissue-resident gamma delta T-cells to target hepatocellular carcinoma
Many cancer immune therapy approaches depend on an HLA-restricted neoantigen-specific T cell response. AUs show here that Zoledronic acid can expand, and induce tumour recognition by, a population of tissue resident memory gamma-delta T cells associated with an efficient anti-tumour immune response in hepatocellular carcinoma.
- Nekisa Zakeri
- , Andrew Hall
- & Mala K. Maini
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Article
| Open AccessThe aberrant upregulation of exon 10-inclusive SREK1 through SRSF10 acts as an oncogenic driver in human hepatocellular carcinoma
Alternative splicing is dysregulated in hepatocellular carcinoma. Here, the authors investigate the role of the splice variant of Splicing Regulatory Glutamic Acid and Lysine Rich Protein 1 (SREK1) and its upstream regulator, Serine/arginine-rich splicing factor 10 (SRSF10) in sustaining the oncogenic signal.
- Cunjie Chang
- , Muthukumar Rajasekaran
- & Jianxiang Chen
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Article
| Open AccessDeep proteomic profiling unveils arylsulfatase A as a non-alcoholic steatohepatitis inducible hepatokine and regulator of glycemic control
Non-alcoholic steatohepatitis (NASH) and type 2 diabetes are closely linked, but the connecting pathophysiological mechanisms are incompletely understood. Here the authors identify arylsulfatase A as a NASH-induced hepatokine that inhibits hepatic lysophosphatidylcholine and lysophosphatidic acid secretion, and improves muscle insulin action and systemic glucose homeostasis.
- Magdalene K. Montgomery
- , Jacqueline Bayliss
- & Matthew J. Watt
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Article
| Open AccessSIRT1 selectively exerts the metabolic protective effects of hepatocyte nicotinamide phosphoribosyltransferase
NAD + metabolism is potential target to treat metabolic disorders, in part due to the effects of the NAD + dependent enzyme Sirt1. Here the authors report that hepatic nicotinamide phosphoribosyltransferase, a rate-limiting step in the NAD + salvage pathway, regulates dark-cycle thermogenesis in a Sirt1-dependent but light-cycle thermogenesis and glucose homeostasis in a Sirt1-independent manner.
- Cassandra B. Higgins
- , Allyson L. Mayer
- & Brian J. DeBosch
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Article
| Open AccessThe E3 ubiquitin-protein ligase Trim31 alleviates non-alcoholic fatty liver disease by targeting Rhbdf2 in mouse hepatocytes
Nonalcoholic steatohepatitis (NASH) is a chronic liver disease with complex disease mechanisms. Here the authors report that the E3 ubiquitin-protein ligase Trim31 mitigates development of NASH via inhibition of rhomboid 5 homolog 2 (Rhbdf2) in mice.
- Minxuan Xu
- , Jun Tan
- & Bochu Wang
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Article
| Open AccessKindlin-2 haploinsufficiency protects against fatty liver by targeting Foxo1 in mice
Here, the authors show that expression of kindlin-2 is increased in patients with nonalcoholic fatty liver disease (NAFLD). In mouse models, specific deletion of kindlin-2 in liver ameliorates, while its overexpression exacerbates, NAFLD by modulating Foxo1 in hepatocytes.
- Huanqing Gao
- , Liang Zhou
- & Guozhi Xiao
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Article
| Open AccessFormyl peptide receptor 2 determines sex-specific differences in the progression of nonalcoholic fatty liver disease and steatohepatitis
Prevalence of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) higher in men than premenopausal women. Here the authors report that formyl peptide receptor 2 (FPR2) levels are regulated by estrogen, and that FPR2 contributes to NAFLD resistance in female mice.
- Chanbin Lee
- , Jieun Kim
- & Youngmi Jung
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Article
| Open AccessDepletion of mitochondrial methionine adenosyltransferase α1 triggers mitochondrial dysfunction in alcohol-associated liver disease
Lower activity of MATα1, which catalyzes the synthesis of the methyl donor S-adenosylmethionine, and mitochondrial dysfunction occur in alcohol-associated liver disease (ALD). Here the authors report that the peptidyl-prolyl cis/trans isomerase PIN1 mediates a selective depletion of MATα1 in the mitochondria, which contributes to mitochondrial dysfunction and fat accumulation, in mouse models of ALD.
- Lucía Barbier-Torres
- , Ben Murray
- & Shelly C. Lu
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Article
| Open AccessMaternal regulation of biliary disease in neonates via gut microbial metabolites
The pathogenesis of biliary atresia remains poorly understood. Here, the authors report that maternal butyrate treatment alters the gut microbiome and glutamine/hypoxanthine metabolites similar to human subjects, and suppresses biliary atresia in newborn mice.
- Jai Junbae Jee
- , Li Yang
- & Jorge A. Bezerra
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Article
| Open AccessThe methyltransferase METTL3 negatively regulates nonalcoholic steatohepatitis (NASH) progression
Mechanisms that underlie the progression of non-alcoholic fatty liver disease to the more severe non-alcoholic steatohepatitis are incompletely understood. Here the authors show that METTL3, a RNA methyltransferase that catalyzes mRNA m6 modifications, negatively regulates NASH progression via inhibiting the transcription of Cd36 and Ccl2.
- Xinzhi Li
- , Bingchuan Yuan
- & Zheng Chen
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Article
| Open AccessSpatial Transcriptomics to define transcriptional patterns of zonation and structural components in the mouse liver
Global transcriptional differences across lobular units in the liver remain unknown. Here the authors perform spatial transcriptomics of liver tissue to delineate transcriptional differences in physical space, confirm lobular zonation along transcriptional gradients and suggest the presence of previously uncharacterized structures within liver tissue.
- Franziska Hildebrandt
- , Alma Andersson
- & Johan Ankarklev
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| Open AccessHigher intake of whole grains and dietary fiber are associated with lower risk of liver cancer and chronic liver disease mortality
Higher intake of dietary fiber and whole grains are associated with reduced risk of various diseases including some cancers. Here, the authors estimate reductions in liver cancer of 22% and 31% and chronic liver disease mortality of 56% and 63% associated with increased whole grain and dietary fiber intake, respectively.
- Xing Liu
- , Wanshui Yang
- & Xuehong Zhang
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Article
| Open AccessN1-methyladenosine methylation in tRNA drives liver tumourigenesis by regulating cholesterol metabolism
Metabolic adaptation has been reported to promote cancer, yet the underlying mechanisms are not clear. Here, the authors show that m1A methylation in tRNA regulates cholesterol metabolism in liver cancer stem cells and m1A inhibition decreases tumourigenesis in preclinical models of hepatocellular carcinoma.
- Yanying Wang
- , Jing Wang
- & Zusen Fan
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Article
| Open AccessA human multi-lineage hepatic organoid model for liver fibrosis
Autosomal recessive polycystic kidney disease (ARPKD) is a genetic disorder which is associated with kidney and liver pathology, including liver fibrosis. Here the authors develop and characterize human liver organoids with a ARPKD mutation, and find that they show aspects of the pathology, including fibrosis.
- Yuan Guan
- , Annika Enejder
- & Gary Peltz
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Article
| Open AccessEnvironmental eustress modulates β-ARs/CCL2 axis to induce anti-tumor immunity and sensitize immunotherapy against liver cancer in mice
The impact of positive environment stimulations (eustress) on cancer biology remains poorly understood. Here the authors show that exposure to an environment enrichment stimulates anti-tumor immunity and reduces tumor growth in preclinical models of liver cancer.
- Chaobao Liu
- , Yang Yang
- & Hui Wang
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Article
| Open AccessA phase 2, proof of concept, randomised controlled trial of berberine ursodeoxycholate in patients with presumed non-alcoholic steatohepatitis and type 2 diabetes
Berberine ursodeoxycholate has been studied for its serum lipid and lipoprotein lowering effects. Here the authors report an 18-week phase 2, randomised, double-blind, placebo-controlled clinical trial that tested the effect of berberine ursodeoxycholate in patients with fatty liver disease and diabetes, and showed that the group taking the higher dose of the drug had reduced liver fat content.
- Stephen A. Harrison
- , Nadege Gunn
- & Adrian M. Di Bisceglie
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Article
| Open AccessEfficient intracellular delivery of proteins by a multifunctional chimaeric peptide in vitro and in vivo
Protein delivery with cell-penetrating peptides suffers from ineffective endosomal escape and low tolerance in serum, thereby limiting treatment success. Here the authors present an intracellular protein delivery system and demonstrate efficient delivery in vitro and therapeutic efficacy in a liver failure model in vivo.
- Siyuan Yu
- , Han Yang
- & Ningshao Xia
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Article
| Open AccessSuper enhancer regulation of cytokine-induced chemokine production in alcoholic hepatitis
Alcoholic hepatitis is characterized by intense liver inflammation driven by excessive cytokines and chemokines production and immune cell infiltration. Here the authors identify a super-enhancer that regulates the expression of multiple CXCL chemokines in alcoholic hepatitis and may be a potential therapeutic target.
- Mengfei Liu
- , Sheng Cao
- & Vijay H. Shah
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Article
| Open AccessCD8+ tissue-resident memory T cells promote liver fibrosis resolution by inducing apoptosis of hepatic stellate cells
The cellular and molecular mechanisms underlying the resolution of non-alcoholic steatohepatitis remain incompletely understood. Here the authors report a single cell-based analysis that identified CD8 + tissue-resident memory T cells, which contribute to resolution of liver fibrosis potentially via elimination of hepatic stellate cells through Fas-mediated cytotoxicity.
- Yuzo Koda
- , Toshiaki Teratani
- & Nobuhiro Nakamoto
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Article
| Open AccessMeasurement of lipogenic flux by deuterium resolved mass spectrometry
Fat synthesis is necessary for normal physiology, but its dysregulation contributes to the pathology of many diseases. Here, the authors report a high-resolution mass spectrometry approach that quantifies fat synthesis flux in humans and mice following a brief and low dose of deuterated water.
- Xiaorong Fu
- , Stanisław Deja
- & Shawn C. Burgess
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Article
| Open AccessEnsembled deep learning model outperforms human experts in diagnosing biliary atresia from sonographic gallbladder images
It is still challenging to make accurate diagnosis of biliary atresia (BA) with sonographic gallbladder images particularly in rural areas without relevant expertise. Here, the authors develop a diagnostic deep learning model which favourable performance in comparison with human experts in multi-center external validation.
- Wenying Zhou
- , Yang Yang
- & Luyao Zhou
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Matters Arising
| Open AccessHypothermic machine perfusion before viability testing of previously discarded human livers
- Otto B. van Leeuwen
- , Yvonne de Vries
- & Robert J. Porte
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Matters Arising
| Open AccessReply to ‘Hypothermic machine perfusion before viability testing of previously discarded human livers’
- Hynek Mergental
- , Richard W. Laing
- & Darius F. Mirza
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Article
| Open AccessGenome-wide association study of serum liver enzymes implicates diverse metabolic and liver pathology
Serum liver enzymes are used as markers of liver disease, their concentration influenced in part by genetic factors. Here the authors meta-analyse genome-wide association studies on the UK Biobank and BioBank Japan to evaluate the association of three liver enzymes with liver and other metabolic diseases.
- Vincent L. Chen
- , Xiaomeng Du
- & Elizabeth K. Speliotes
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Article
| Open AccessCD4 derived double negative T cells prevent the development and progression of nonalcoholic steatohepatitis
Hepatic inflammation contributes to the development of nonalcoholic steatohepatitis (NASH). Here, the authors show that a transfer of ex vivo generated CD4 derived double negative T cells can prevent the development and progression of NASH by suppression of inflammatory Th17 cells and M1 macrophages in mouse models.
- Guangyong Sun
- , Xinyan Zhao
- & Dong Zhang
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Article
| Open AccessLysosomal SLC46A3 modulates hepatic cytosolic copper homeostasis
The environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) causes hepatic toxicity associated with prominent lipid accumulation in humans. Here, the authors report that the lysosomal copper transporter SLC46A3 is induced by TCDD and underlies the hepatic lipid accumulation in mice, potentially via effects on mitochondrial function.
- Jung-Hwan Kim
- , Tsutomu Matsubara
- & Frank J. Gonzalez
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Article
| Open AccessHigh-fat diet-induced upregulation of exosomal phosphatidylcholine contributes to insulin resistance
High-fat diet plays a role in development of insulin resistance. Here, the authors report a mechanism that underlies the development of diet induced insulin resistance through the activation of an aryl hydrocarbon receptor mediated signalling pathway in the liver by faecal exosomes derived from intestinal cells.
- Anil Kumar
- , Kumaran Sundaram
- & Huang-Ge Zhang
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Article
| Open AccessGut microbiota impact on the peripheral immune response in non-alcoholic fatty liver disease related hepatocellular carcinoma
Disease-specific gut microbiome signatures have been previously defined for patients with liver cirrhosis or hepatocellular carcinoma (HCC). Here the authors examine the composition of the gut microbiota in cirrhotic patients with non-alcoholic fatty liver disease with or without HCC and evaluate how dysbiosis influences peripheral immune responses.
- Jason Behary
- , Nadia Amorim
- & Amany Zekry
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Article
| Open AccessHepatitis B virus rigs the cellular metabolome to avoid innate immune recognition
RIG-I is a cytosolic antiviral nucleic acid sensor that signals via MAVS to produce type 1 interferons. Here the authors show that hepatits B virus can repress this pathway by activating glycolysis and lactate production, enabling accumulated lactate to bind MAVS and prevent its mitochondrial localization.
- Li Zhou
- , Rui He
- & Shi Liu
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Article
| Open AccessHepatocyte-specific IL11 cis-signaling drives lipotoxicity and underlies the transition from NAFLD to NASH
IL11 contributes to the development of non-alcoholic steatohepatitis (NASH) through incompletely understood mechanisms. Here, the authors report that lipotoxicity-driven autocrine IL11 activity underlies hepatocyte metabolic dysfunction and death via a NOX4/ERK-mediated mechanism while paracrine IL11 activity stimulates hepatic stellate cells contributing to fibrosis and inflammation in the context of NASH.
- Jinrui Dong
- , Sivakumar Viswanathan
- & Anissa A. Widjaja
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Article
| Open AccessAdipoR1/AdipoR2 dual agonist recovers nonalcoholic steatohepatitis and related fibrosis via endoplasmic reticulum-mitochondria axis
Nonalcoholic steatohepatitis (NASH) and associated liver fibrosis have limited therapy options. Here the authors report a novel adiponectin-based dual agonist for adiponectin receptors 1 and 2 with a longer half-life, and show that it ameliorates NASH and liver fibrosis in mouse models.
- Hongjiao Xu
- , Qian Zhao
- & Xianxing Jiang