RT Journal Article
T1 RIPK3 acts as a lipid metabolism regulator contributing to inflammation and carcinogenesis in non-alcoholic fatty liver disease.
A1 Afonso, Marta B
A1 Rodrigues, Pedro M
A1 Mateus-Pinheiro, Miguel
A1 Simão, André L
A1 Gaspar, Maria M
A1 Majdi, Amine
A1 Arretxe, Enara
A1 Alonso, Cristina
A1 Santos-Laso, Alvaro
A1 Jimenez-Agüero, Raul
A1 Eizaguirre, Emma
A1 Bujanda, Luis
A1 Pareja, Maria Jesus
A1 Banales, Jesus M
A1 Ratziu, Vlad
A1 Gautheron, Jeremie
A1 Castro, Rui E
A1 Rodrigues, Cecília M P
K1 cell death
K1 chronic liver disease
K1 lipid metabolism
K1 molecular carcinogenesis
K1 nonalcoholic steatohepatitis
AB Receptor-interacting protein kinase 3 (RIPK3) is a key player in necroptosis execution and an emerging metabolic regulator, whose contribution to non-alcoholic fatty liver disease (NAFLD) is controversial. We aimed to clarify the impact of RIPK3 signalling in the pathogenesis of human and experimental NAFLD. RIPK3 levels were evaluated in two large independent cohorts of patients with biopsy proven NAFLD diagnosis and correlated with clinical and biochemical parameters. Wild-type (WT) or Ripk3-deficient (Ripk3-/-) mice were fed a choline-deficient L-amino acid-defined diet (CDAA) or an isocaloric control diet for 32 and 66 weeks. RIPK3 increased in patients with non-alcoholic steatohepatitis (NASH) in both cohorts, correlating with hepatic inflammation and fibrosis. Accordingly, Ripk3 deficiency ameliorated CDAA-induced inflammation and fibrosis in mice at both 32 and 66 weeks. WT mice on the CDAA diet for 66 weeks developed preneoplastic nodules and displayed increased hepatocellular proliferation, which were reduced in Ripk3-/- mice. Furthermore, Ripk3 deficiency hampered tumourigenesis. Intriguingly, Ripk3-/- mice displayed increased body weight gain, while lipidomics showed that deletion of Ripk3 shifted hepatic lipid profiles. Peroxisome proliferator-activated receptor γ (PPARγ) was increased in Ripk3-/- mice and negatively correlated with hepatic RIPK3 in patients with NAFLD. Mechanistic studies established a functional link between RIPK3 and PPARγ in controlling fat deposition and fibrosis. Hepatic RIPK3 correlates with NAFLD severity in humans and mice, playing a key role in managing liver metabolism, damage, inflammation, fibrosis and carcinogenesis. Targeting RIPK3 and its intricate signalling arises as a novel promising approach to treat NASH and arrest disease progression.
YR 2020
FD 2020-12-24
LK https://hdl.handle.net/10668/27147
UL https://hdl.handle.net/10668/27147
LA en
DS RISalud
RD Apr 8, 2025