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| Open AccessThe pan-PPAR agonist lanifibranor improves cardiometabolic health in patients with metabolic dysfunction-associated steatohepatitis
Cardiovascular events are the main cause of mortality in patients with metabolic dysfunctionassociated steatohepatitis (MASH). Here, the authors show that lanifibranor improves cardiometabolic health - insulin sensitivity, lipid and glucose metabolism, systemic inflammation and hepatic steatosis.
- Michael P. Cooreman
- , Javed Butler
- & Sven M. Francque
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Article
| Open AccessCirculating fatty acids and risk of hepatocellular carcinoma and chronic liver disease mortality in the UK Biobank
Different fatty acids have been associated to liver diseases. Here, the authors show that plasma levels of different circulating fatty acids are either negatively or positively associated with the risk of hepatocellular carcinoma and chronic liver disease mortality in the UK Biobank cohort.
- Zhening Liu
- , Hangkai Huang
- & Chengfu Xu
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Article
| Open AccessA patient-based iPSC-derived hepatocyte model of alcohol-associated cirrhosis reveals bioenergetic insights into disease pathogenesis
Most people affected by Alcohol Use Disorder do not develop cirrhosis. Here, the authors show that induced pluripotent stem cell-derived hepatocytes from patients with Alcohol Cirrhosis, have impaired cell energy production and were more susceptible to oxidative stress, which is partially reversed by treatment with Aramchol.
- Bani Mukhopadhyay
- , Cheryl Marietta
- & David Goldman
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Article
| Open AccessTargeting pathogenic CD8+ tissue-resident T cells with chimeric antigen receptor therapy in murine autoimmune cholangitis
CD8 + T cells play an important role in primary biliary cholangitis (PBC). In this study, the authors demonstrate that PD-1-expressing CD8+ liver-resident T cells are pathogenic in murine PBC and that targeting these cells using a chimaeric antigen receptor reduces disease severity.
- Hao-Xian Zhu
- , Shu-Han Yang
- & Zhe-Xiong Lian
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| Open AccessHarnessing whole human liver ex situ normothermic perfusion for preclinical AAV vector evaluation
Developing clinically predictive model systems for evaluating gene transfer and gene editing technologies has become increasingly important. This study introduces human liver ex situ normothermic perfusion as a model to evaluate gene therapy vectors, paving the way for advanced liver disease treatment.
- Marti Cabanes-Creus
- , Sophia H. Y. Liao
- & Leszek Lisowski
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Article
| Open AccessInhibition of 7-dehydrocholesterol reductase prevents hepatic ferroptosis under an active state of sterol synthesis
Ferroptosis has been connected to liver disease through unclear mechanisms. Here, the authors identify the terminal enzyme of cholesterol synthesis, 7-dehydrocholesterol reductase, as a regulator of ferroptosis in hepatocytes that suppresses ferroptosis through 7-dehydrocholesterol accumulation.
- Naoya Yamada
- , Tadayoshi Karasawa
- & Masafumi Takahashi
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Article
| Open AccessBTLA contributes to acute-on-chronic liver failure infection and mortality through CD4+ T-cell exhaustion
Acute-on-chronic liver failure (ACLF) is characterized by rapid deterioration of liver function in patients with chronic liver disease. Here, the authors show that BTLA expression in CD4+ T cells is associated with disease severity and inflammation in hepatitis B virus-related ACLF.
- Xueping Yu
- , Feifei Yang
- & Jiming Zhang
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Article
| Open AccessSonic hedgehog-heat shock protein 90β axis promotes the development of nonalcoholic steatohepatitis in mice
The mechanistic involvement of sonic hedgehog signaling in nonalcoholic steatohepatitis is not clear. Here, the authors show that sonic hedgehog protein regulates the stability of HSP90β, enabling hepatocytes to secrete exosomes containing miR-28-5-p to promote NASH development.
- Weitao Zhang
- , Junfeng Lu
- & Xiaojun Xu
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Article
| Open AccessHeterogeneity of hepatocyte dynamics restores liver architecture after chemical, physical or viral damage
Hepatocytes regenerate the liver after injury, however, the tissue repair mechanisms have been little explored. Here, the authors show that midlobular and pericentral hepatocytes increase their number and size in response to chemical, physical, and viral insults facilitating liver regeneration.
- Inmaculada Ruz-Maldonado
- , John T. Gonzalez
- & Carlos Fernández-Hernando
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Article
| Open AccessA multicenter clinical AI system study for detection and diagnosis of focal liver lesions
Early detection and accurate diagnosis of focal liver lesions are crucial for effective treatment and prognosis. Here, the authors present a fully automated diagnostic system that leverages multi-phase CT scans and clinical features, for diagnosing liver lesions.
- Hanning Ying
- , Xiaoqing Liu
- & Xiujun Cai
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Article
| Open AccessIdentification of myeloid-derived growth factor as a mechanically-induced, growth-promoting angiocrine signal for human hepatocytes
After partial liver resection, the remaining liver blood vessels receive more blood flow and get mechanically stretched. Here the authors show that MYDGF is released from the stretched cells of these liver vessels, and that it is required and sufficient to promote liver regeneration and cell proliferation.
- Linda Große-Segerath
- , Paula Follert
- & Eckhard Lammert
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Article
| Open AccessIntraocular liver spheroids for non-invasive high-resolution in vivo monitoring of liver cell function
Longitudinal monitoring of liver function in vivo is hindered by the lack of high-resolution non-invasive imaging techniques. Here, the authors show a crucial and unique tool for longitudinal in vivo imaging of liver spheroids at cellular resolution to study liver physiology and disease.
- Francesca Lazzeri-Barcelo
- , Nuria Oliva-Vilarnau
- & Per-Olof Berggren
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Article
| Open AccessMacro CD5L+ deteriorates CD8+T cells exhaustion and impairs combination of Gemcitabine-Oxaliplatin-Lenvatinib-anti-PD1 therapy in intrahepatic cholangiocarcinoma
The role of the tumor microenvironment in immunotherapy response in intrahepatic cholangiocarcinoma remains unclear. Here, single cell RNA and TCR sequencing of samples before and after immunotherapy highlights the role of CD8 T-cell status conversion and exhaustion induced by Macro CD5L+ in treatment response.
- Jia-Cheng Lu
- , Lei-Lei Wu
- & Jia Fan
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Article
| Open AccessFatty acid synthesis suppresses dietary polyunsaturated fatty acid use
Polyunsaturated Fatty Acids (PUFA), such as omega-3 fatty acids, are recognized for their lipid lowering and anti-inflammatory properties. Here, the authors show that endogenous lipid synthesis controls the use of PUFA and thus determine the therapeutic benefit of omega-3 fatty acid supplementation.
- Anna Worthmann
- , Julius Ridder
- & Christian Schlein
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Article
| Open AccessBinge-pattern alcohol consumption and genetic risk as determinants of alcohol-related liver disease
Deaths from alcohol-related liver disease have sharply increased following the Covid-19 pandemic. Here, the authors show that binge-pattern alcohol consumption, genetic factors and the presence of diabetes mellitus confer the greatest risk, allowing targeted interventions for high-risk individuals.
- Chengyi Ding
- , Linda Ng Fat
- & Gautam Mehta
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Article
| Open AccessSenescence-associated 13-HODE production promotes age-related liver steatosis by directly inhibiting catalase activity
Polyunsaturated fatty acid-derived bioactive lipids play critical roles as signalling molecules in metabolic processes. Here, the author show 13-HODE produced by senescent hepatocytes and macrophages activates SREBP1 by directly inhibiting CAT activity and promotes age-related steatosis.
- Jinjie Duan
- , Wenhui Dong
- & Chunjiong Wang
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Article
| Open AccessBile proteome reveals biliary regeneration during normothermic preservation of human donor livers
Normothermic machine perfusion (NMP) is increasingly used for preserving and evaluating donor livers before transplantation. Here, the authors demonstrate increased regenerative protein profiles in the bile of perfused livers considered suitable for transplantation, providing insight into the mechanisms linked to recovery of the biliary tree following ischemia-reperfusion injury.
- Adam M. Thorne
- , Justina C. Wolters
- & Vincent E. de Meijer
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Article
| Open AccessIntestinal Atp8b1 dysfunction causes hepatic choline deficiency and steatohepatitis
Choline is an essential nutrient derived primarily from dietary phosphatidylcholine, and its deficiency causes steatohepatitis. Here, the authors show that intestinal Atp8b1 contributes to choline metabolism through lysoPC absorption and that its dysfunction causes choline deficiency and steatohepatitis.
- Ryutaro Tamura
- , Yusuke Sabu
- & Hisamitsu Hayashi
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| Open AccessZHX2 emerges as a negative regulator of mitochondrial oxidative phosphorylation during acute liver injury
Mitochondria dysfunction contributes to acute liver injuries. Zhang et al. find that Zhx2 deletion enhances mitochondrial function by promoting electron transport chain gene expression via PGC-1α dependent and independent manner.
- Yankun Zhang
- , Yuchen Fan
- & Chunhong Ma
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| Open AccessA randomised Phase IIa trial of amine oxidase copper-containing 3 (AOC3) inhibitor BI 1467335 in adults with non-alcoholic steatohepatitis
The authors report data from a Phase IIa randomised, double-blind trial in patients with NASH showing that BI 1467335 strongly and dose-dependently inhibited AOC3 activity (involved in hepatic inflammation) and was well tolerated at all tested doses.
- Philip N. Newsome
- , Arun J. Sanyal
- & Eric Lawitz
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Article
| Open AccessBroad-spectrum kinome profiling identifies CDK6 upregulation as a driver of lenvatinib resistance in hepatocellular carcinoma
Acquired resistance to cancer therapies can develop due to kinase rewiring. Here, using a broad-spectrum chemical probe, the authors perform kinome screening and identify CDK6-mediated accumulation of cancer stem cells as a driver of lenvatinib (multitargeted tyrosine kinase inhibitor) resistance in hepatocellular carcinoma.
- Carmen Oi Ning Leung
- , Yang Yang
- & Terence Kin Wah Lee
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Article
| Open AccessThe mitochondrial fusion protein OPA1 is dispensable in the liver and its absence induces mitohormesis to protect liver from drug-induced injury
The role of the mitochondrial fusion protein OPA1 in liver function is unknown. Here, authors showed that OPA1 is dispensable in the liver, and that the mitohormesis induced by OPA1 deletion prevents liver injury and contributes to liver resiliency.
- Hakjoo Lee
- , Tae Jin Lee
- & Yisang Yoon
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Article
| Open AccessRING finger protein 13 protects against nonalcoholic steatohepatitis by targeting STING-relayed signaling pathways
The STING-relayed inflammation response has been increasingly identified as one of the key drivers of NAFLD progression. Here the authors show that an E3 ubiquitin ligase, RNF13, can ameliorate NAFLD phenotypes by facilitating the TRIM29-mediated degradation of STING.
- Zhibin Lin
- , Peijun Yang
- & Lin Wang
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Article
| Open AccessFibroblast growth factor 18 stimulates the proliferation of hepatic stellate cells, thereby inducing liver fibrosis
Fibroblast growth factor (FGF)18 plays pleiotropic roles, including bone development and carcinogenesis, however, its precise role in liver fibrosis remains incompletely understood. Here, the authors show that FGF18 promotes liver fibrosis by stimulating hepatic stellate cell proliferation, without concomitant upregulation of profibrotic genes.
- Yuichi Tsuchiya
- , Takao Seki
- & Hiroyasu Nakano
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Article
| Open AccessURI alleviates tyrosine kinase inhibitors-induced ferroptosis by reprogramming lipid metabolism in p53 wild-type liver cancers
Despite being a promising treatment for hepatocellular carcinoma (HCC), resistance to tyrosine kinase inhibitors (TKI) present a major obstacle. Here, the authors demonstrate that lipid metabolism reprogramming via URI mediated stearoyl-CoA desaturase 1 upregulation present a targetable driver of sorafenib resistance in HCC.
- Zhiwen Ding
- , Yufei Pan
- & Lu Wang
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Article
| Open AccessPractical diagnosis of cirrhosis in non-alcoholic fatty liver disease using currently available non-invasive fibrosis tests
The practical rules for the early non-invasive diagnosis of cirrhosis in NAFLD are not well defined. Here, the authors develop and validate two diagnostic tools: a stepwise stratification algorithm including a cirrhosis group, and a risk prediction chart providing a personalized assessment of the individual probability of cirrhosis.
- Jérôme Boursier
- , Marine Roux
- & Philip N. Newsome
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Article
| Open Accessp21-activated kinase 4 suppresses fatty acid β-oxidation and ketogenesis by phosphorylating NCoR1
PPARα corepressor NCoR1 is a key regulator of fatty acid β-oxidation and ketogenesis. Here, the authors demonstrate that p21-activated kinase 4 phosphorylates NCoR1 at T1619/T2124, resulting in PPARα transrepression and ketone body reduction.
- Min Yan Shi
- , Hwang Chan Yu
- & Eun Ju Bae
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Article
| Open AccessLong-term ex situ normothermic perfusion of human split livers for more than 1 week
Long-term machine perfusion of human livers outside the body is an emerging field with tremendous potential for the assessment, recovery, and modification of organs prior to transplantation. Here, the authors report the long-term ex situ perfusion of human livers and demonstrate the ability to split and perfuse these organs using a standardised protocol.
- Ngee-Soon Lau
- , Mark Ly
- & Carlo Pulitano
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Article
| Open AccessUSP25 regulates KEAP1-NRF2 anti-oxidation axis and its inactivation protects acetaminophen-induced liver injury in male mice
The redox status of a cell is regulated through a number of mechanisms, chief among these is the KEAP1-mediated ubiquitination and degradation of NRF2. Here the authors show that KEAP1 itself is ubiquitinated and degraded in a process that is opposed by the ubiquitin-specific protease USP25.
- Changzhou Cai
- , Huailu Ma
- & Jiewei Wang
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Article
| Open AccessIn vivo PAR-CLIP (viP-CLIP) of liver TIAL1 unveils targets regulating cholesterol synthesis and secretion
Here the authors develop viP-CLIP, a technique allowing the identification of RNA binding proteins (RBP) targets in mouse tissues, and identify the RBP Tial1 as a regulator of cholesterol metabolism in the liver.
- Hasan Vatandaslar
- , Aitor Garzia
- & Markus Stoffel
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Article
| Open AccessColitis ameliorates cholestatic liver disease via suppression of bile acid synthesis
The association between primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD) has been known for decades, but mechanisms of gut-liver crosstalk are incompletely understood. Here, the authors show a colitis-triggered protective circuit suppressing cholestatic liver disease which encourages multi-organ treatment strategies for PSC.
- Wenfang Gui
- , Mikal Jacob Hole
- & Kai Markus Schneider
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| Open AccessBacteriophage therapy against pathological Klebsiella pneumoniae ameliorates the course of primary sclerosing cholangitis
Patients with primary sclerosing cholangitis (PSC) harboring Klebsiella pneumoniae (Kp) exhibit poor clinical outcomes. Here, the authors show that administration of a phage cocktail targeting PSC-derived Kp reduces bacterial burden in Kp-colonized mice and alleviates liver injury.
- Masataka Ichikawa
- , Nobuhiro Nakamoto
- & Takanori Kanai
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| Open AccessBacteriophage targeting microbiota alleviates non-alcoholic fatty liver disease induced by high alcohol-producing Klebsiella pneumoniae
Previous studies have shown that high alcohol-producing Klebsiella pneumoniae (HiAlc Kpn) in the intestinal microbiome could be one of the causes of non-alcoholic fatty liver disease (NAFLD). Here, the authors show the effectiveness of phage in mice with HiAlc Kpn-induced NAFLD indicating phage therapy targeting gut microbiota may be an alternative to antibiotics, with potential efficacy and safety.
- Lin Gan
- , Yanling Feng
- & Jing Yuan
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| Open AccessRegorafenib inhibits EphA2 phosphorylation and leads to liver damage via the ERK/MDM2/p53 axis
The mechanism underlying regorafenib’s hepatotoxicity during anticancer therapy remains elusive. Here, the authors show regorafenib inhibits the phosphorylation of EphA2 at Ser897 resulting in the accumulation of p53 and contributes to hepatocytes apoptosis and the formation of hepatotoxicity.
- Hao Yan
- , Wentong Wu
- & Peihua Luo
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Article
| Open AccessAlternative promoters in CpG depleted regions are prevalently associated with epigenetic misregulation of liver cancer transcriptomes
The regulatory mechanisms of alternative promoters remain to be investigated. Here, the authors explore the sequence and epigenetics landscape of alternative promoters and how they regulate gene expression in hepatocellular carcinoma.
- Chirag Nepal
- & Jesper B. Andersen
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Article
| Open AccessLysosomal-associated protein transmembrane 5 ameliorates non-alcoholic steatohepatitis by promoting the degradation of CDC42 in mice
Non-alcoholic steatohepatitis (NASH) has received great attention due to its high incidence, but the underlying mechanism remains poorly understood. Here, the authors show LAPTM5 expression ameliorates NASH and can potentially serve as a biological marker indicative of NASH progression.
- Lang Jiang
- , Jing Zhao
- & Jiahong Xia
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Article
| Open AccessRestoration of lysosomal acidification rescues autophagy and metabolic dysfunction in non-alcoholic fatty liver disease
In NAFLD, high levels of fatty acids in the liver impair lysosomal acidification. Here, the authors report the synthesis of novel biodegradable acid-activated acidifying nanoparticles that re-acidify lysosomes, restore autophagy, and reverse fasting hyperglycemia and hepatic steatosis in fat mice.
- Jialiu Zeng
- , Rebeca Acin-Perez
- & Mark W. Grinstaff
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Article
| Open AccessParabacteroides distasonis ameliorates hepatic fibrosis potentially via modulating intestinal bile acid metabolism and hepatocyte pyroptosis in male mice
Parabacteroides distasonis (P. distasonis), part of the gut microbiome, was reported to play a role in diabetes, colorectal cancer and inflammatory bowel disease. Here the authors report that P. distasonis ameliorates liver fibrosis in studies with male mice, potentially via altered bile acid metabolism and hepatocyte pyroptosis.
- Qi Zhao
- , Man-Yun Dai
- & Fei Li
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Article
| Open AccessA regulatory variant at 19p13.3 is associated with primary biliary cholangitis risk and ARID3A expression
Primary biliary cholangitis is a rare, chronic immune-mediated liver disease triggered by environmental exposures in genetically susceptible individuals. Here, the authors investigate the functional mechanism underlying the association of 19p13.3 variants with primary biliary cholangitis.
- You Li
- , Zhiqiang Li
- & Xiong Ma
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Article
| Open AccessEarly life gut microbiota sustains liver-resident natural killer cells maturation via the butyrate-IL-18 axis
Liver-resident natural killer cells develop locally and have multiple immunological roles in situ. Here the authors investigate the gut-liver axis and show the impact of the intestinal microbiota on the development of liver-resident natural killer cells.
- Panpan Tian
- , Wenwen Yang
- & Xiaohong Liang
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Article
| Open AccessEnhanced Ca2+-channeling complex formation at the ER-mitochondria interface underlies the pathogenesis of alcohol-associated liver disease
Ca2+ overload-induced mitochondrial dysfunction is considered a contributing factor alcohol-associated liver disease pathogenesis. Here the authors report that PDK4 promotes Ca2 + -channelling complex formation at the endoplasmic reticulum-mitochondria contact sites, which contributes to the pathogenesis of alcohol-associated liver disease in studies with male mouse and hepatocyte models.
- Themis Thoudam
- , Dipanjan Chanda
- & In-Kyu Lee
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Article
| Open AccessAcute liver steatosis translationally controls the epigenetic regulator MIER1 to promote liver regeneration in a study with male mice
Early lipid accumulation is thought to contribute to liver regeneration through unclear functional mechanisms. Here the authors identify an epigenetic regulator, MIER1, that bridges the acute lipid accumulation and cell cycle gene transcription during liver regeneration after surgical resection in male mice.
- Yanhao Chen
- , Lanlan Chen
- & Qiurong Ding
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Article
| Open AccessClinically important alterations in pharmacogene expression in histologically severe nonalcoholic fatty liver disease
This study characterizes expression of pharmacogenes across the histological NAFLD severity spectrum. Here, the authors show the downregulation of CYP2C19 in NAFLD which supports developing personalized medicine approaches for drugs sensitive to metabolism by the CYP2C19 enzyme.
- Nicholas R. Powell
- , Tiebing Liang
- & Naga Chalasani
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Article
| Open AccessDeficiency of gluconeogenic enzyme PCK1 promotes metabolic-associated fatty liver disease through PI3K/AKT/PDGF axis activation in male mice
Phosphoenolpyruvate carboxykinase 1 (Pck1) is an enzyme involved in glucose production that also regulates lipogenesis and has been linked to liver steatosis. Here the authors report that deficiency of Pck1 in the liver leads to nonalcoholic fatty liver disease via activation of the RhoA/PI3K/AKT pathway in a study with male mice.
- Qian Ye
- , Yi Liu
- & Ni Tang
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Article
| Open AccessGut microbiota alters host bile acid metabolism to contribute to intrahepatic cholestasis of pregnancy
Intrahepatic cholestasis of pregnancy (ICP) is a liver disease that sometimes develops during pregnancy and is characterized by increased serum bile acid levels. Here the authors report that the gut microbiome species B. fragilis is enriched in patients with ICP and promotes ICP development in mice via inhibition of signalling though the bile acid receptor FXR.
- Bo Tang
- , Li Tang
- & Shiming Yang
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Article
| Open AccessMolecular imaging of liver inflammation using an anti-VCAM-1 nanobody
Here, the authors present a noninvasive tool to detect liver inflammation using nuclear imaging, as an alternative to biopsy. The prove the diagnostic power of this tool to detect liver inflammation in preclinical models of chronic liver disease.
- Maxime Nachit
- , Christopher Montemagno
- & Pascale Perret
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Article
| Open AccessMicrobially produced vitamin B12 contributes to the lipid-lowering effect of silymarin
Silymarin has been used for improving hepatic damage and lipid disorders, but its action mechanism remains to be clarified. Here, the authors reveal a mechanism of action underpinning the lipid-lowering effect of silymarin via the gut microbiota and its vitamin B12 producing capabilities.
- Wen-Long Sun
- , Sha Hua
- & Hong-Fang Ji
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| Open AccessWestern diet contributes to the pathogenesis of non-alcoholic steatohepatitis in male mice via remodeling gut microbiota and increasing production of 2-oleoylglycerol
Interplay of western diet and gut microbiota has been reported to be involved in the development of nonalcoholic steatohepatitis (NASH). Here the authors report that Blautia producta and 2-oleoylglycerol are bacterial and metabolic mediators that promote liver inflammation and hepatic fibrosis in male mice.
- Ming Yang
- , Xiaoqiang Qi
- & Guangfu Li
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Article
| Open AccessSystematic review and individual-patient-data meta-analysis of non-invasive fibrosis markers for chronic hepatitis B in Africa
Authors carry out a systematic review and meta-analysis to evaluate the performance of fibrosis biomarkers for the diagnosis of fibrosis and cirrhosis in patients with chronic hepatitis B virus infection living in sub-Saharan Africa.
- Asgeir Johannessen
- , Alexander J. Stockdale
- & Maud Lemoine