PSD3 downregulation confers protection against fatty liver disease.
Rosellina Margherita Mancina
(1)
,
K. Sasidharan
(1)
,
A. Lindblom
(2)
,
Y. Wei
(3)
,
Ester Ciociola
(1)
,
Oveis Jamialahmadi
(1)
,
P. Pingitore
(1)
,
Anne-Christine Andréasson
(2)
,
G. Pellegrini
(2)
,
G. Baselli
(4, 5)
,
V. Männistö
(6, 7)
,
J. Pihlajamäki
(6, 7)
,
V. Kärjä
(6, 7)
,
S. Grimaudo
(8)
,
I. Marini
(4, 5)
,
M. Maggioni
(4)
,
B. Becattini
(1)
,
F. Tavaglione
(1)
,
C. Dix
(9)
,
M. Castaldo
(2)
,
S. Klein
(3)
,
M. Perelis
(3)
,
Francois Pattou
(10, 11, 12)
,
Dorothée Thuillier
(10, 11, 12)
,
Violeta Raverdy
(10, 11, 12)
,
P. Dongiovanni
(4)
,
A. L. Fracanzani
(4, 5)
,
F. Stickel
(13)
,
J. Hampe
(14, 15)
,
S. Buch
(14, 15)
,
P. K. Luukkonen
(16, 17, 18, 19)
,
D. Prati
(4, 5)
,
H. Yki-Järvinen
(16, 17, 18)
,
S. Petta
(8)
,
C. Xing
(20)
,
C. Schafmayer
(21)
,
E. Aigner
(22)
,
C. Datz
(22)
,
R. G. Lee
(3)
,
L. Valenti
(4, 5)
,
D. Lindén
(2, 1)
,
S. Romeo
(1, 23, 24)
1
GU -
Göteborgs Universitet = University of Gothenburg
2 AstraZeneca
3 Ionis Pharmaceuticals, USA
4 IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico [Milano, Italia]
5 UNIMI - Università degli Studi di Milano = University of Milan
6 University of Eastern Finland
7 KUH - Kuopio University Hospital
8 Università degli studi di Palermo - University of Palermo
9 AstraZeneca [Cambridge, UK]
10 RTD - Recherche translationnelle sur le diabète - U 1190
11 CHRU Lille - Centre Hospitalier Régional Universitaire [CHU Lille]
12 EGID - Institut Européen de Génomique du Diabète - European Genomic Institute for Diabetes - FR 3508
13 University hospital of Zurich [Zurich]
14 University Hospital Carl Gustav Carus [Dresden, Germany]
15 TU Dresden - Technische Universität Dresden = Dresden University of Technology
16 Helsingin yliopisto = Helsingfors universitet = University of Helsinki
17 HUS - Helsinki University Hospital [Finland]
18 Minerva Foundation Institute for Medical Research
19 Yale University [New Haven]
20 University of Texas Southwestern Medical Center [Dallas]
21 University of Rostock
22 PMU - Paracelsus Medizinische Privatuniversität = Paracelsus Medical University
23 Sahlgrenska University Hospital [Gothenburg]
24 UMG - Università degli Studi "Magna Graecia" di Catanzaro = University of Catanzaro
2 AstraZeneca
3 Ionis Pharmaceuticals, USA
4 IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico [Milano, Italia]
5 UNIMI - Università degli Studi di Milano = University of Milan
6 University of Eastern Finland
7 KUH - Kuopio University Hospital
8 Università degli studi di Palermo - University of Palermo
9 AstraZeneca [Cambridge, UK]
10 RTD - Recherche translationnelle sur le diabète - U 1190
11 CHRU Lille - Centre Hospitalier Régional Universitaire [CHU Lille]
12 EGID - Institut Européen de Génomique du Diabète - European Genomic Institute for Diabetes - FR 3508
13 University hospital of Zurich [Zurich]
14 University Hospital Carl Gustav Carus [Dresden, Germany]
15 TU Dresden - Technische Universität Dresden = Dresden University of Technology
16 Helsingin yliopisto = Helsingfors universitet = University of Helsinki
17 HUS - Helsinki University Hospital [Finland]
18 Minerva Foundation Institute for Medical Research
19 Yale University [New Haven]
20 University of Texas Southwestern Medical Center [Dallas]
21 University of Rostock
22 PMU - Paracelsus Medizinische Privatuniversität = Paracelsus Medical University
23 Sahlgrenska University Hospital [Gothenburg]
24 UMG - Università degli Studi "Magna Graecia" di Catanzaro = University of Catanzaro
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.