ArticleNature metabolism2022
PSD3 downregulation confers protection against fatty liver disease.
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Article in Nature metabolism, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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25 citing papers in PubMed.
- Cyclodipeptides Reversed Liver Damage and Adipose Tissue Dysfunction in a Chronic Obesity MASLD Rat Model by Remodeling White Adipocytes Toward a Beige-like Adipocyte Phenotype.Molecules (Basel, Switzerland) · 2026Article
- Hepatic Lipoprotein Production, Cardiometabolic Phenotypes, and Subtypes of Steatotic Liver Disease.Circulation research · 2026Review
- Germline mutations and somatic mosaicism in steatotic liver diseases and related liver carcinogenesis.Nature reviews. Gastroenterology & hepatology · 2026Review
- Chemical Genetic Screen Identifies PSD3 as a Direct Substrate of NUAK1 that Regulates Dendritic Spine Maturation.bioRxiv : the preprint server for biology · 2026Article
- Metabolic dysfunction-associated steatotic liver disease and steatohepatitis-associated hepatocarcinoma preclinical models.Nature reviews. Gastroenterology & hepatology · 2026Review
- Genomic structural equation modeling reveals shared genetic structure of cardiac function and structure-function association studies of CLCNKA mutations.Scientific reports · 2026Article
- Primary Human Tissue Models for Metabolic Dysfunction-Associated Liver Disease - toward Streamlining Drug Discovery with Patient-Derived Assays.Advanced biology · 2025Review
- Human genetics of steatotic liver disease: insights into insulin resistance and lipid metabolism.Nature metabolism · 2025Review
- Immune and genetic landscapes of biliary atresia: a pathway to precision medicine.BMC pediatrics · 2025Article
- Gene-based therapies for steatotic liver disease.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Review
- Downregulation of the MARC1 p.A165 risk allele reduces hepatocyte lipid content by increasing beta-oxidation.Clinical and molecular hepatology · 2025Article
- Precision medicine and nucleotide-based therapeutics to treat steatotic liver disease.Clinical and molecular hepatology · 2025Review
- Article
- The contribution of genetics and epigenetics to MAFLD susceptibility.Hepatology international · 2024Review
- Longitudinal integrative cell-free DNA analysis in gestational diabetes mellitus.Cell reports. Medicine · 2024Article
- Reorganization of 3D genome architecture provides insights into pathogenesis of early fatty liver disease in laying hens.Journal of animal science and biotechnology · 2024Article
- Drug targets regulate systemic metabolism and provide new horizons to treat nonalcoholic steatohepatitis.Metabolism open · 2024Review
- Article
- Knockout of STE20-type kinase TAOK3 does not attenuate diet-induced NAFLD development in mice.Molecular medicine (Cambridge, Mass.) · 2023Article
- Emerging novel targets for nonalcoholic fatty liver disease treatment: Evidence from recent basic studies.World journal of gastroenterology · 2023Review
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Authors and funding
42 authors.
Rosellina M Mancina *Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden.ORCID http://orcid.org/0000-0002-1126-3071
Kavitha Sasidharan *Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden.ORCID http://orcid.org/0000-0003-3706-4692
Anna LindblomBioscience Metabolism, Research and Early Development Cardiovascular, Renal and Metabolism (CVRM) BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.ORCID http://orcid.org/0000-0003-4903-1759
Ying WeiIonis Pharmaceuticals, Carlsbad, CA, USA.
Ester CiociolaDepartment of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden.
Oveis JamialahmadiDepartment of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden.
Piero PingitoreDepartment of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden.
Anne-Christine AndréassonBioscience Cardiovascular, Research and Early Development Cardiovascular, Renal and Metabolism (CVRM) BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
Giovanni PellegriniPathology, Clinical Pharmacology and Safety Sciences BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
Guido BaselliTranslational Medicine, Department of Transfusion Medicine and Hematology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico and Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy.ORCID http://orcid.org/0000-0002-0234-6828
Ville MännistöDepartment of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.
Jussi PihlajamäkiInstitute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland.ORCID http://orcid.org/0000-0002-6241-6859
Vesa KärjäDepartment of Pathology, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.
Stefania GrimaudoSection of Gastroenterology and Hepatology, PROMISE, University of Palermo, Palermo, Italy.
Ilaria MariniTranslational Medicine, Department of Transfusion Medicine and Hematology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico and Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy.
Marco MaggioniDepartment of Pathology, Fondazione Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
Barbara BecattiniDepartment of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden.
Federica TavaglioneDepartment of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden.
Carly DixAntibody Discovery and Protein Engineering (ADPE), AstraZeneca, Cambridge, UK.
Marie CastaldoDiscovery Biology, Discovery Sciences R&D, AstraZeneca, Gothenburg, Sweden.
Stephanie KleinIonis Pharmaceuticals, Carlsbad, CA, USA.
Mark PerelisIonis Pharmaceuticals, Carlsbad, CA, USA.
Francois PattouUniversity of Lille, Inserm, Lille Pasteur Institute, CHU Lille, European Genomic Institute for Diabetes, U1190 Translational Research in Diabetes, Lille University, Lille, France.ORCID http://orcid.org/0000-0001-8388-3766
Dorothée ThuillierUniversity of Lille, Inserm, Lille Pasteur Institute, CHU Lille, European Genomic Institute for Diabetes, U1190 Translational Research in Diabetes, Lille University, Lille, France.
Violeta RaverdyUniversity of Lille, Inserm, Lille Pasteur Institute, CHU Lille, European Genomic Institute for Diabetes, U1190 Translational Research in Diabetes, Lille University, Lille, France.
Paola DongiovanniGeneral Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
Anna Ludovica FracanzaniGeneral Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
Felix StickelDepartment of Gastroenterology and Hepatology, University Hospital of Zurich, Zurich, Switzerland.
Jochen HampeMedical Department 1, University Hospital Dresden, Technische Universitaät Dresden (TU Dresden), Dresden, Germany.ORCID http://orcid.org/0000-0002-2421-6127
Stephan BuchMedical Department 1, University Hospital Dresden, Technische Universitaät Dresden (TU Dresden), Dresden, Germany.ORCID http://orcid.org/0000-0003-2928-015X
Panu K LuukkonenDepartment of Medicine, University of Helsinki and Helsinki University Central Hosptial, Helsinki, Finland.
Daniele PratiTranslational Medicine, Department of Transfusion Medicine and Hematology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico and Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy.
Hannele Yki-JärvinenDepartment of Medicine, University of Helsinki and Helsinki University Central Hosptial, Helsinki, Finland.
Salvatore PettaSection of Gastroenterology and Hepatology, PROMISE, University of Palermo, Palermo, Italy.
Chao XingMcDermott Center for Human Growth and Development University of Texas Southwestern Medical Center, Dallas, TX, USA.ORCID http://orcid.org/0000-0002-1838-0502
Clemens SchafmayerDepartment of General, Visceral, Vascular and Transplantation Surgery, University of Rostock, Rostock, Germany.
Elmar AignerFirst Department of Medicine, Paracelsus Medical University, Salzburg, Austria.
Christian DatzDepartment of Internal Medicine, General Hospital Oberndorf, Teaching Hospital of the Paracelsus Medical University Salzburg, Oberndorf, Austria.ORCID http://orcid.org/0000-0001-7838-4532
Richard G LeeIonis Pharmaceuticals, Carlsbad, CA, USA.
Luca ValentiTranslational Medicine, Department of Transfusion Medicine and Hematology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico and Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy.
Daniel LindénBioscience Metabolism, Research and Early Development Cardiovascular, Renal and Metabolism (CVRM) BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden. daniel.linden@astrazeneca.com.ORCID http://orcid.org/0000-0003-4158-8018
Stefano RomeoDepartment of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden. stefano.romeo@wlab.gu.se.ORCID http://orcid.org/0000-0001-9168-4898
Funding
No grant is acknowledged in the PubMed record.
Abstract
Fatty liver disease (FLD) is a growing health issue with burdening unmet clinical needs. FLD has a genetic component but, despite the common variants already identified, there is still a missing heritability component. Using a candidate gene approach, we identify a locus (rs71519934) at the Pleckstrin and Sec7 domain-containing 3 (PSD3) gene resulting in a leucine to threonine substitution at position 186 of the protein (L186T) that reduces susceptibility to the entire spectrum of FLD in individuals at risk. PSD3 downregulation by short interfering RNA reduces intracellular lipid content in primary human hepatocytes cultured in two and three dimensions, and in human and rodent hepatoma cells. Consistent with this, Psd3 downregulation by antisense oligonucleotides in vivo protects against FLD in mice fed a non-alcoholic steatohepatitis-inducing diet. Thus, translating these results to humans, PSD3 downregulation might be a future therapeutic option for treating FLD.
Indexed as
Disease SusceptibilityGene Expression RegulationAllelesAnimalsBiomarkersCell LineFatty LiverGene Expression ProfilingGenetic VariationGenotypeGuanine Nucleotide Exchange FactorsHepatocytesHumansLiverMicePolymorphism, Single NucleotideBiomarkersGuanine Nucleotide Exchange FactorsPSD4 protein, humanRibonucleasesRNS1 protein, Arabidopsis
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