PSD3 downregulation confers protection against fatty liver disease

Rosellina M. Mancina, Kavitha Sasidharan, Anna Lindblom, Ying Wei, Ester Ciociola, Oveis Jamialahmadi, Piero Pingitore, Anne Christine Andréasson, Giovanni Pellegrini, Guido Baselli, Ville Männistö, Jussi Pihlajamäki, Vesa Kärjä, Stefania Grimaudo, Ilaria Marini, Marco Maggioni, Barbara Becattini, Federica Tavaglione, Carly Dix, Marie CastaldoStephanie Klein, Mark Perelis, Francois Pattou, Dorothée Thuillier, Violeta Raverdy, Paola Dongiovanni, Anna Ludovica Fracanzani, Felix Stickel, Jochen Hampe, Stephan Buch, Panu K. Luukkonen, Daniele Prati, Hannele Yki-Järvinen, Salvatore Petta, Chao Xing, Clemens Schafmayer, Elmar Aigner, Christian Datz, Richard G. Lee, Luca Valenti, Daniel Lindén, Stefano Romeo

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)60-75
Number of pages16
JournalNature Metabolism
Volume4
Issue number1
DOIs
StatePublished - Jan 2022

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Cell Biology
  • Physiology (medical)

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