TY - JOUR
T1 - PSD3 downregulation confers protection against fatty liver disease
AU - Mancina, Rosellina M.
AU - Sasidharan, Kavitha
AU - Lindblom, Anna
AU - Wei, Ying
AU - Ciociola, Ester
AU - Jamialahmadi, Oveis
AU - Pingitore, Piero
AU - Andréasson, Anne Christine
AU - Pellegrini, Giovanni
AU - Baselli, Guido
AU - Männistö, Ville
AU - Pihlajamäki, Jussi
AU - Kärjä, Vesa
AU - Grimaudo, Stefania
AU - Marini, Ilaria
AU - Maggioni, Marco
AU - Becattini, Barbara
AU - Tavaglione, Federica
AU - Dix, Carly
AU - Castaldo, Marie
AU - Klein, Stephanie
AU - Perelis, Mark
AU - Pattou, Francois
AU - Thuillier, Dorothée
AU - Raverdy, Violeta
AU - Dongiovanni, Paola
AU - Fracanzani, Anna Ludovica
AU - Stickel, Felix
AU - Hampe, Jochen
AU - Buch, Stephan
AU - Luukkonen, Panu K.
AU - Prati, Daniele
AU - Yki-Järvinen, Hannele
AU - Petta, Salvatore
AU - Xing, Chao
AU - Schafmayer, Clemens
AU - Aigner, Elmar
AU - Datz, Christian
AU - Lee, Richard G.
AU - Valenti, Luca
AU - Lindén, Daniel
AU - Romeo, Stefano
N1 - Funding Information:
We thank Julia Kozlitina at University of Texas Southwestern Medical Center, Dallas, TX for the analysis of the DHS data. This work was supported by a project grant from the Swedish Research Council (Vetenskapsradet (VR), 2021-005208) (S.R.), the Swedish state under the Agreement between the Swedish government and the county councils (the ALF agreement, SU 2018-04276) (S.R.), the Swedish Diabetes Foundation (DIA2020-518) (S.R.), the Swedish Heart Lung Foundation (20200191) (S.R.), the Wallenberg Academy Fellows from the Knut and Alice Wallenberg Foundation (KAW 2017.0203) (S.R.), the Novonordisk Project grants in Endocrinology and Metabolism (NNF20OC0063883) (S.R.), AstraZeneca Agreement for Research, and Grant SSF ITM17-0384 (S.R.), Swedish Foundation for Strategic Research (S.R.), the MyFirst Grant AIRC n.16888, Ricerca Finalizzata Ministero della Salute RF-2016-02364358 (L.V.), Ricerca Corrente Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico (L.V.) and the European Union (EU) Programme Horizon 2020 (under grant agreement no. 777377) for the project LITMUS–‘Liver Investigation: Testing Marker Utility in Steatohepatitis’ (L.V.).
Funding Information:
A provisional patent application directed to the subject matter disclosed in this manuscript has been filed. A.L., A.-C.A., G.P., C. Dix, M.C. and D.L. are AstraZeneca employees. Y.W., S.K., M.P. and R.G.L. are Ionis Pharmaceuticals employees. S.R. has served as a consultant for AstraZeneca, Celgene, Sanofi, Amgen, Akcea Therapeutics, Camp4, Medacorp and Pfizer in the last 5 years. S.R. has received research grants from AstraZeneca, Sanofi and Amgen. L.V. reports having received speaking fees from MSD, Gilead, AlfaSigma, and AbbVie, having served as a consultant for Gilead, Pfizer, Astra Zeneca, Novo Nordisk, and having received research grants from Gilead. PKL was supported by the Novo Nordisk, Sigrid Jusélius and Instrumentarium Science Foundations. The remaining authors declare no competing interests.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/1
Y1 - 2022/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s42255-021-00518-0
DO - 10.1038/s42255-021-00518-0
M3 - Article
C2 - 35102341
AN - SCOPUS:85123974742
SN - 2522-5812
VL - 4
SP - 60
EP - 75
JO - Nature Metabolism
JF - Nature Metabolism
IS - 1
ER -