PSD3 downregulation confers protection against fatty liver disease.

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.

• Authors: 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 Castaldo, Stephanie 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
• Journal: Nature metabolism (Nat Metab) Vol. 4 Issue 1 Pg. 60-75 (01 2022) ISSN: 2522-5812 [Electronic] Germany
• PMID: 35102341 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s).

Chemical References

• Biomarkers
• Guanine Nucleotide Exchange Factors
• PSD4 protein, human
• RNS1 protein, Arabidopsis
• Ribonucleases

Topics

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