PSD3 downregulation confers protection against fatty liver disease.

Alleles Animals Biomarkers Cell Line Disease Susceptibility Fatty Liver / etiology Gene Expression Profiling Gene Expression Regulation Genetic Variation Genotype Guanine Nucleotide Exchange Factors / genetics Hepatocytes / metabolism Humans Liver / metabolism Mice Polymorphism, Single Nucleotide RNA-Seq Ribonucleases

Journal

Nature metabolism
ISSN: 2522-5812
Titre abrégé: Nat Metab
Pays: Germany
ID NLM: 101736592

Informations de publication

Date de publication:
01 2022
Historique:
received: 23 08 2021
accepted: 08 12 2021
entrez: 1 2 2022
pubmed: 2 2 2022
medline: 1 3 2022
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1038/s42255-021-00518-0 PMID: 35102341 PMC: PMC8803605
pubmed: 35102341
doi: 10.1038/s42255-021-00518-0
pii: 10.1038/s42255-021-00518-0
pmc: PMC8803605
doi:

Substances chimiques

Biomarkers 0
Guanine Nucleotide Exchange Factors 0
PSD4 protein, human 0
RNS1 protein, Arabidopsis EC 3.1.-
Ribonucleases EC 3.1.-

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

60-75

Informations de copyright

© 2022. The Author(s).

Références

Younossi, Z. & Henry, L. Contribution of alcoholic and nonalcoholic fatty liver disease to the burden of liver-related morbidity and mortality. Gastroenterology 150, 1778–1785 (2016).
pubmed: 26980624 doi: 10.1053/j.gastro.2016.03.005
Eslam, M. et al. A new definition for metabolic dysfunction-associated fatty liver disease: An international expert consensus statement. J. Hepatol. 73, 202–209 (2020).
pubmed: 32278004 doi: 10.1016/j.jhep.2020.03.039
Estes, C. et al. Modeling NAFLD disease burden in China, France, Germany, Italy, Japan, Spain, United Kingdom, and United States for the period 2016–2030. J. Hepatol. 69, 896–904 (2018).
pubmed: 29886156 doi: 10.1016/j.jhep.2018.05.036
Armstrong, M. J. et al. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet 387, 679–690 (2016).
pubmed: 26608256 doi: 10.1016/S0140-6736(15)00803-X
Neuschwander-Tetri, B. A. et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet 385, 956–965 (2015).
pubmed: 25468160 doi: 10.1016/S0140-6736(14)61933-4
Pelusi, S. & Valenti, L. Hepatic fat as clinical outcome and therapeutic target for nonalcoholic fatty liver disease. Liver Int 39, 250–256 (2019).
pubmed: 30248234 doi: 10.1111/liv.13972
Eslam, M., Valenti, L. & Romeo, S. Genetics and epigenetics of NAFLD and NASH: clinical impact. J. Hepatol. 68, 268–279 (2018).
pubmed: 29122391 doi: 10.1016/j.jhep.2017.09.003
Loomba, R. et al. Heritability of hepatic fibrosis and steatosis based on a prospective twin study. Gastroenterology 149, 1784–1793 (2015).
pubmed: 26299412 doi: 10.1053/j.gastro.2015.08.011
Makkonen, J., Pietilainen, K. H., Rissanen, A., Kaprio, J. & Yki-Jarvinen, H. Genetic factors contribute to variation in serum alanine aminotransferase activity independent of obesity and alcohol: a study in monozygotic and dizygotic twins. J. Hepatol. 50, 1035–1042 (2009).
pubmed: 19303161 doi: 10.1016/j.jhep.2008.12.025
van Beek, J. H. et al. Heritability of liver enzyme levels estimated from genome-wide SNP data. Eur. J. Hum. Genet. 23, 1223–1228 (2015).
pubmed: 25424715 doi: 10.1038/ejhg.2014.259
Vinkhuyzen, A. A., Wray, N. R., Yang, J., Goddard, M. E. & Visscher, P. M. Estimation and partition of heritability in human populations using whole-genome analysis methods. Annu. Rev. Genet. 47, 75–95 (2013).
pubmed: 23988118 pmcid: 4037293 doi: 10.1146/annurev-genet-111212-133258
Kozlitina, J. et al. Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease. Nat. Genet. 46, 352–356 (2014).
pubmed: 24531328 pmcid: 3969786 doi: 10.1038/ng.2901
Mancina, R. M. et al. The MBOAT7-TMC4 variant rs641738 increases risk of nonalcoholic fatty liver disease in individuals of European descent. Gastroenterology 150, 1219–1230 (2016).
pubmed: 26850495 doi: 10.1053/j.gastro.2016.01.032
Romeo, S. et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat. Genet. 40, 1461–1465 (2008).
pubmed: 18820647 pmcid: 2597056 doi: 10.1038/ng.257
Speliotes, E. K. et al. Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits. PLoS Genet. 7, e1001324 (2011).
pubmed: 21423719 pmcid: 3053321 doi: 10.1371/journal.pgen.1001324
Carlsson, B. et al. Review article: the emerging role of genetics in precision medicine for patients with non-alcoholic steatohepatitis. Aliment. Pharmcol. Ther. 51, 1305–1320 (2020).
doi: 10.1111/apt.15738
Romeo, S., Sanyal, A. & Valenti, L. Leveraging human genetics to identify potential new treatments for fatty liver disease. Cell Metab. 31, 35–45 (2020).
pubmed: 31914377 doi: 10.1016/j.cmet.2019.12.002
Teslovich, T. M. et al. Biological, clinical and population relevance of 95 loci for blood lipids. Nature 466, 707–713 (2010).
pubmed: 20686565 pmcid: 3039276 doi: 10.1038/nature09270
Adiels, M. et al. Overproduction of large VLDL particles is driven by increased liver fat content in man. Diabetologia 49, 755–765 (2006).
pubmed: 16463046 doi: 10.1007/s00125-005-0125-z
Diraison, F. & Beylot, M. Role of human liver lipogenesis and reesterification in triglycerides secretion and in FFA reesterification. Am. J. Physiol. 274, E321–E327 (1998).
pubmed: 9486165
Fabbrini, E. et al. Alterations in adipose tissue and hepatic lipid kinetics in obese men and women with nonalcoholic fatty liver disease. Gastroenterology 134, 424–431 (2008).
pubmed: 18242210 doi: 10.1053/j.gastro.2007.11.038
Gibbons, G. F. Assembly and secretion of hepatic very-low-density lipoprotein. Biochem. J. 268, 1–13 (1990).
pubmed: 2188646 pmcid: 1131384 doi: 10.1042/bj2680001
Salter, A. M., Wiggins, D., Sessions, V. A. & Gibbons, G. F. The intracellular triacylglycerol/fatty acid cycle: a comparison of its activity in hepatocytes which secrete exclusively apolipoprotein (apo) B100 very-low-density lipoprotein (VLDL) and in those which secrete predominantly apoB48 VLDL. Biochem. J. 332, 667–672 (1998).
pubmed: 9620868 pmcid: 1219526 doi: 10.1042/bj3320667
Dongiovanni, P. et al. Transmembrane 6 superfamily member 2 gene variant disentangles nonalcoholic steatohepatitis from cardiovascular disease. Hepatology 61, 506–514 (2015).
pubmed: 25251399 doi: 10.1002/hep.27490
Stender, S. et al. Adiposity amplifies the genetic risk of fatty liver disease conferred by multiple loci. Nat. Genet. 49, 842–847 (2017).
pubmed: 28436986 pmcid: 5562020 doi: 10.1038/ng.3855
Thangapandi, V. R. et al. Loss of hepatic Mboat7 leads to liver fibrosis. Gut 70, 940–950 (2021).
pubmed: 32591434 doi: 10.1136/gutjnl-2020-320853
Baselli, G. A. et al. Liver transcriptomics highlights interleukin-32 as novel NAFLD-related cytokine and candidate biomarker. Gut 69, 1855–1866 (2020).
pubmed: 32001554 doi: 10.1136/gutjnl-2019-319226
Kleiner, D. E. et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 41, 1313–1321 (2005).
pubmed: 15915461 doi: 10.1002/hep.20701
Abul-Husn, N. S. et al. A protein-truncating HSD17B13 variant and protection from chronic liver disease. N. Engl. J. Med. 378, 1096–1106 (2018).
pubmed: 29562163 pmcid: 6668033 doi: 10.1056/NEJMoa1712191
Luukkonen, P. K. et al. MARC1 variant rs2642438 increases hepatic phosphatidylcholines and decreases severity of non-alcoholic fatty liver disease in humans. J. Hepatol. 73, 725–726 (2020).
pubmed: 32471727 doi: 10.1016/j.jhep.2020.04.021
Jamialahmadi, O. et al. Exome-wide association study on alanine aminotransferase identifies sequence variants in the GPAM and APOE associated with fatty liver disease. Gastroenterology 160, 1634–1646.e1637 (2021).
pubmed: 33347879 doi: 10.1053/j.gastro.2020.12.023
Suvichapanich, S. et al. Genomewide association study confirming the association of NAT2 with susceptibility to antituberculosis drug-induced liver injury in thai patients. Antimicrob. Agents Chemother. 63, e02692-18 (2019).
pubmed: 31109976 pmcid: 6658740 doi: 10.1128/AAC.02692-18
D’Souza-Schorey, C. & Chavrier, P. ARF proteins: roles in membrane traffic and beyond. Nat. Rev. Mol. Cell Biol. 7, 347–358 (2006).
pubmed: 16633337 doi: 10.1038/nrm1910
Wang, Y. et al. Large scale identification of human hepatocellular carcinoma-associated antigens by autoantibodies. J. Immunol. 169, 1102–1109 (2002).
pubmed: 12097419 doi: 10.4049/jimmunol.169.2.1102
Dongiovanni, P. et al. Causal relationship of hepatic fat with liver damage and insulin resistance in nonalcoholic fatty liver. J. Intern. Med. 283, 356–370 (2018).
pubmed: 29280273 doi: 10.1111/joim.12719
Tanaka, Y. et al. LPIAT1/MBOAT7 depletion increases triglyceride synthesis fueled by high phosphatidylinositol turnover. Gut 70, 180–193 (2021).
pubmed: 32253259 doi: 10.1136/gutjnl-2020-320646
Victor, R. G. et al. The Dallas Heart Study: a population-based probability sample for the multidisciplinary study of ethnic differences in cardiovascular health. Am. J. Cardiol. 93, 1473–1480 (2004).
pubmed: 15194016 doi: 10.1016/j.amjcard.2004.02.058
Szczepaniak, L. S. et al. Measurement of intracellular triglyceride stores by H spectroscopy: validation in vivo. Am. J. Physiol. 276, E977–E989 (1999).
pubmed: 10329993
Luukkonen, P. K. et al. Hepatic ceramides dissociate steatosis and insulin resistance in patients with non-alcoholic fatty liver disease. J. Hepatol. 64, 1167–1175 (2016).
pubmed: 26780287 doi: 10.1016/j.jhep.2016.01.002
Valenti, L. et al. The APOC3 T-455C and C-482T promoter region polymorphisms are not associated with the severity of liver damage independently of PNPLA3 I148M genotype in patients with nonalcoholic fatty liver. J. Hepatol. 55, 1409–1414 (2011).
pubmed: 21777557 doi: 10.1016/j.jhep.2011.03.035
Petta, S. et al. Glucokinase regulatory protein gene polymorphism affects liver fibrosis in non-alcoholic fatty liver disease. PLoS ONE 9, e87523 (2014).
pubmed: 24498332 pmcid: 3911959 doi: 10.1371/journal.pone.0087523
Simonen, M. et al. Desmosterol in human nonalcoholic steatohepatitis. Hepatology 58, 976–982 (2013).
pubmed: 23447451 doi: 10.1002/hep.26342
Canela-Xandri, O., Rawlik, K. & Tenesa, A. An atlas of genetic associations in UK Biobank. Nat. Genet. 50, 1593–1599 (2018).
pubmed: 30349118 pmcid: 6707814 doi: 10.1038/s41588-018-0248-z
Crawford, K. et al. Medical consequences of pathogenic CNVs in adults: analysis of the UK Biobank. J. Med. Genet. 56, 131–138 (2019).
pubmed: 30343275 doi: 10.1136/jmedgenet-2018-105477
Linge, J. et al. Body composition profiling in the UK Biobank imaging study. Obesity 26, 1785–1795 (2018).
pubmed: 29785727 doi: 10.1002/oby.22210
Linge, J., Whitcher, B., Borga, O. & Dahlqvist Leinhard, O. Sub‐phenotyping metabolic disorders using body composition: an individualized, nonparametric approach utilizing large data sets. Obesity (Silver Spring) 27, 1190–1199 (2019).
doi: 10.1002/oby.22510
Bycroft, C. et al. The UK Biobank resource with deep phenotyping and genomic data. Nature 562, 203–209 (2018).
pubmed: 30305743 pmcid: 6786975 doi: 10.1038/s41586-018-0579-z
Sudlow, C. et al. UK Biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age. PLoS Med. 12, e1001779 (2015).
pubmed: 25826379 pmcid: 4380465 doi: 10.1371/journal.pmed.1001779
Prill, S. et al. The TM6SF2 E167K genetic variant induces lipid biosynthesis and reduces apolipoprotein B secretion in human hepatic 3D spheroids. Sci. Rep. 9, 11585 (2019).
pubmed: 31406127 pmcid: 6690969 doi: 10.1038/s41598-019-47737-w
Graham, M. J. et al. Antisense oligonucleotide inhibition of apolipoprotein C-III reduces plasma triglycerides in rodents, nonhuman primates, and humans. Circ. Res. 112, 1479–1490 (2013).
pubmed: 23542898 doi: 10.1161/CIRCRESAHA.111.300367
Patro, R., Duggal, G., Love, M. I., Irizarry, R. A. & Kingsford, C. Salmon provides fast and bias-aware quantification of transcript expression. Nat. Methods 14, 417–419 (2017).
pubmed: 28263959 pmcid: 5600148 doi: 10.1038/nmeth.4197
Pingitore, P. et al. PNPLA3 overexpression results in reduction of proteins predisposing to fibrosis. Hum. Mol. Genet. 25, 5212–5222 (2016).
pubmed: 27742777 pmcid: 5886043
Pirazzi, C. et al. Patatin-like phospholipase domain-containing 3 (PNPLA3) I148M (rs738409) affects hepatic VLDL secretion in humans and in vitro. J. Hepatol. 57, 1276–1282 (2012).
pubmed: 22878467 doi: 10.1016/j.jhep.2012.07.030
Ölander, M. et al. A simple approach for restoration of differentiation and function in cryopreserved human hepatocytes. Arch. Toxicol. 93, 819–829 (2019).
pubmed: 30560367 doi: 10.1007/s00204-018-2375-9
Pingitore, P. et al. Human multilineage 3D spheroids as a model of liver steatosis and fibrosis. Int. J. Mol. Sci. 20, 1629 (2019).
pmcid: 6480107 doi: 10.3390/ijms20071629
Lindén, D., Sjöberg, A., Asp, L., Carlsson, L. & Oscarsson, J. Direct effects of growth hormone on production and secretion of apolipoprotein B from rat hepatocytes. Am. J. Physiol. Endocrinol. Metab. 279, E1335–E1346 (2000).
pubmed: 11093922 doi: 10.1152/ajpendo.2000.279.6.E1335
Folch, J., Lees, M. & Sloane Stanley, G. H. A simple method for the isolation and purification of total lipides from animal tissues. J. Biol. Chem. 226, 497–509 (1957).
pubmed: 13428781 doi: 10.1016/S0021-9258(18)64849-5
Hansson, P. K., Asztély, A. K., Clapham, J. C. & Schreyer, S. A. Glucose and fatty acid metabolism in McA-RH7777 hepatoma cells vs. rat primary hepatocytes: responsiveness to nutrient availability. Biochim. Biophys. Acta 1684, 54–62 (2004).
pubmed: 15450210 doi: 10.1016/j.bbalip.2004.06.005
Østergaard, M. E. et al. Efficient synthesis and biological evaluation of 5′-GalNAc conjugated antisense oligonucleotides. Bioconjug. Chem. 26, 1451–1455 (2015).
pubmed: 26011654 doi: 10.1021/acs.bioconjchem.5b00265
Drescher, H. The influence of different fat sources on steatohepatitis and fibrosis development in the western diet mouse model of non-alcoholic steatohepatitis (NASH). Front. Physiol. 10, 770 (2019).
pubmed: 31293441 pmcid: 6603084 doi: 10.3389/fphys.2019.00770
Carr, T. P., Andresen, C. J. & Rudel, L. L. Enzymatic determination of triglyceride, free cholesterol, and total cholesterol in tissue lipid extracts. Clin. Biochem. 26, 39–42 (1993).
pubmed: 8448837 doi: 10.1016/0009-9120(93)90015-X
Balduzzi, S., Rücker, G. & Schwarzer, G. How to perform a meta-analysis with R: a practical tutorial. Evid. Based Ment. Health 22, 153–160 (2019).
pubmed: 31563865 doi: 10.1136/ebmental-2019-300117

Auteurs

Rosellina M Mancina (RM)

Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden.
ORCID: 0000-0002-1126-3071

Kavitha Sasidharan (K)

Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden.
ORCID: 0000-0003-3706-4692

Anna Lindblom (A)

Bioscience Metabolism, Research and Early Development Cardiovascular, Renal and Metabolism (CVRM) BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
ORCID: 0000-0003-4903-1759

Ying Wei (Y)

Ionis Pharmaceuticals, Carlsbad, CA, USA.

Ester Ciociola (E)

Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden.

Oveis Jamialahmadi (O)

Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden.

Piero Pingitore (P)

Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden.

Anne-Christine Andréasson (AC)

Bioscience Cardiovascular, Research and Early Development Cardiovascular, Renal and Metabolism (CVRM) BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.

Giovanni Pellegrini (G)

Pathology, Clinical Pharmacology and Safety Sciences BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.

Guido Baselli (G)

Translational 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: 0000-0002-0234-6828

Ville Männistö (V)

Department of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.

Jussi Pihlajamäki (J)

Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland.
Clinical Nutrition and Obesity Centre, Kuopio University Hospital, Kuopio, Finland.
ORCID: 0000-0002-6241-6859

Vesa Kärjä (V)

Department of Pathology, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.

Stefania Grimaudo (S)

Section of Gastroenterology and Hepatology, PROMISE, University of Palermo, Palermo, Italy.

Ilaria Marini (I)

Translational 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 Maggioni (M)

Department of Pathology, Fondazione Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

Barbara Becattini (B)

Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden.

Federica Tavaglione (F)

Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden.

Carly Dix (C)

Antibody Discovery and Protein Engineering (ADPE), AstraZeneca, Cambridge, UK.

Marie Castaldo (M)

Discovery Biology, Discovery Sciences R&D, AstraZeneca, Gothenburg, Sweden.

Stephanie Klein (S)

Ionis Pharmaceuticals, Carlsbad, CA, USA.

Mark Perelis (M)

Ionis Pharmaceuticals, Carlsbad, CA, USA.

Francois Pattou (F)

University of Lille, Inserm, Lille Pasteur Institute, CHU Lille, European Genomic Institute for Diabetes, U1190 Translational Research in Diabetes, Lille University, Lille, France.
CHU Lille, Department of General and Endocrine Surgery, Intergrated Center for Obesity, Lille, France.
ORCID: 0000-0001-8388-3766

Dorothée Thuillier (D)

University of Lille, Inserm, Lille Pasteur Institute, CHU Lille, European Genomic Institute for Diabetes, U1190 Translational Research in Diabetes, Lille University, Lille, France.

Violeta Raverdy (V)

University of Lille, Inserm, Lille Pasteur Institute, CHU Lille, European Genomic Institute for Diabetes, U1190 Translational Research in Diabetes, Lille University, Lille, France.
CHU Lille, Department of General and Endocrine Surgery, Intergrated Center for Obesity, Lille, France.

Paola Dongiovanni (P)

General Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

Anna Ludovica Fracanzani (AL)

General Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy.

Felix Stickel (F)

Department of Gastroenterology and Hepatology, University Hospital of Zurich, Zurich, Switzerland.

Jochen Hampe (J)

Medical Department 1, University Hospital Dresden, Technische Universitaät Dresden (TU Dresden), Dresden, Germany.
ORCID: 0000-0002-2421-6127

Stephan Buch (S)

Medical Department 1, University Hospital Dresden, Technische Universitaät Dresden (TU Dresden), Dresden, Germany.
ORCID: 0000-0003-2928-015X

Panu K Luukkonen (PK)

Department of Medicine, University of Helsinki and Helsinki University Central Hosptial, Helsinki, Finland.
Minerva Foundation Institute for Medical Research, Helsinki, Finland.
Department of Internal Medicine, Yale University, New Haven, CT, USA.

Daniele Prati (D)

Translational 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-Järvinen (H)

Department of Medicine, University of Helsinki and Helsinki University Central Hosptial, Helsinki, Finland.
Minerva Foundation Institute for Medical Research, Helsinki, Finland.

Salvatore Petta (S)

Section of Gastroenterology and Hepatology, PROMISE, University of Palermo, Palermo, Italy.

Chao Xing (C)

McDermott Center for Human Growth and Development University of Texas Southwestern Medical Center, Dallas, TX, USA.
ORCID: 0000-0002-1838-0502

Clemens Schafmayer (C)

Department of General, Visceral, Vascular and Transplantation Surgery, University of Rostock, Rostock, Germany.

Elmar Aigner (E)

First Department of Medicine, Paracelsus Medical University, Salzburg, Austria.

Christian Datz (C)

Department of Internal Medicine, General Hospital Oberndorf, Teaching Hospital of the Paracelsus Medical University Salzburg, Oberndorf, Austria.
ORCID: 0000-0001-7838-4532

Richard G Lee (RG)

Ionis Pharmaceuticals, Carlsbad, CA, USA.

Luca Valenti (L)

Translational 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 Lindén (D)

Bioscience Metabolism, Research and Early Development Cardiovascular, Renal and Metabolism (CVRM) BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden. daniel.linden@astrazeneca.com.
Division of Endocrinology, Department of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. daniel.linden@astrazeneca.com.
ORCID: 0000-0003-4158-8018

Stefano Romeo (S)

Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden. stefano.romeo@wlab.gu.se.
Department of Cardiology, Sahlgrenska University Hospital, Gothenburg, Sweden. stefano.romeo@wlab.gu.se.
Clinical Nutrition Unit, Department of Medical and Surgical Sciences, University Magna Graecia, Catanzaro, Italy. stefano.romeo@wlab.gu.se.
ORCID: 0000-0001-9168-4898

Articles similaires

[Redispensing of expensive oral anticancer medicines: a practical application].

Lisanne N van Merendonk, Kübra Akgöl, Bastiaan Nuijen
1.00
Humans Antineoplastic Agents Administration, Oral Drug Costs Counterfeit Drugs

Smoking Cessation and Incident Cardiovascular Disease.

Jun Hwan Cho, Seung Yong Shin, Hoseob Kim et al.
1.00
Humans Male Smoking Cessation Cardiovascular Diseases Female

Evaluation of Low-Value Services Across Major Medicare Advantage Insurers and Traditional Medicare.

Ciara Duggan, Adam L Beckman, Ishani Ganguli et al.
1.00
Humans United States Aged Cross-Sectional Studies Medicare Part C

Effectiveness of Virtual Yoga for Chronic Low Back Pain: A Randomized Clinical Trial.

Hallie Tankha, Devyn Gaskins, Amanda Shallcross et al.
1.00
Humans Yoga Low Back Pain Female Male

Classifications MeSH

questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Génome › Composants de génome › Gènes › Allèles › PSD3 downregulation confers protection against...
questionsmedicales.fr › Eucaryotes › Animaux › PSD3 downregulation confers protection against...
questionsmedicales.fr › Facteurs biologiques › Marqueurs biologiques › PSD3 downregulation confers protection against...
questionsmedicales.fr › Cellules › Cellules cultivées › Lignée cellulaire › PSD3 downregulation confers protection against...
questionsmedicales.fr › Phénomènes physiologiques › Constitution physique › Prédisposition aux maladies › PSD3 downregulation confers protection against...
questionsmedicales.fr › Maladies de l'appareil digestif › Maladies du foie › Stéatose hépatique › PSD3 downregulation confers protection against...
questionsmedicales.fr › Techniques d'investigation › Techniques génétiques › Analyse de profil d'expression de gènes › PSD3 downregulation confers protection against...
questionsmedicales.fr › Phénomènes génétiques › Régulation de l'expression des gènes › PSD3 downregulation confers protection against...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › PSD3 downregulation confers protection against...
questionsmedicales.fr › Phénomènes génétiques › Génotype › PSD3 downregulation confers protection against...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Régulateurs des protéines G › Facteurs d'échange de nucléotides guanyliques › PSD3 downregulation confers protection against...
questionsmedicales.fr › Cellules › Cellules épithéliales › Hépatocytes › PSD3 downregulation confers protection against...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › PSD3 downregulation confers protection against...
questionsmedicales.fr › Système digestif › Foie › PSD3 downregulation confers protection against...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › PSD3 downregulation confers protection against...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Polymorphisme génétique › Polymorphisme de nucléotide simple › PSD3 downregulation confers protection against...
questionsmedicales.fr › Techniques d'investigation › Techniques génétiques › Analyse de séquence › Analyse de séquence d'ARN › RNA-Seq › PSD3 downregulation confers protection against...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Hydrolases › Esterases › Ribonucléases › PSD3 downregulation confers protection against...