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Liver osteopontin is required to prevent the progression of age‐related nonalcoholic fatty liver disease.

Authors :
Gómez‐Santos, Beatriz
Saenz de Urturi, Diego
Nuñez‐García, Maitane
Gonzalez‐Romero, Francisco
Buque, Xabier
Aurrekoetxea, Igor
Gutiérrez de Juan, Virginia
Gonzalez‐Rellan, Maria J.
García‐Monzón, Carmelo
González‐Rodríguez, Águeda
Mosteiro, Lorena
Errazti, Gaizka
Mifsut, Patricia
Gaztambide, Sonia
Castaño, Luis
Martin, Cesar
Nogueiras, Rubén
Martinez‐Chantar, María L.
Syn, Wing‐Kin
Aspichueta, Patricia
Source :
Aging Cell; Aug2020, Vol. 19 Issue 8, p1-16, 16p
Publication Year :
2020

Abstract

Osteopontin (OPN), a senescence‐associated secretory phenotype factor, is increased in patients with nonalcoholic fatty liver disease (NAFLD). Cellular senescence has been associated with age‐dependent hepatosteatosis. Thus, we investigated the role of OPN in the age‐related hepatosteatosis. For this, human serum samples, animal models of aging, and cell lines in which senescence was induced were used. Metabolic fluxes, lipid, and protein concentration were determined. Among individuals with a normal liver, we observed a positive correlation between serum OPN levels and increasing age. This correlation with age, however, was absent in patients with NAFLD. In wild‐type (WT) mice, serum and liver OPN were increased at 10 months old (m) along with liver p53 levels and remained elevated at 20m. Markers of liver senescence increased in association with synthesis and concentration of triglycerides (TG) in 10m OPN‐deficient (KO) hepatocytes when compared to WT hepatocytes. These changes in senescence and lipid metabolism in 10m OPN‐KO mice liver were associated with the decrease of 78 kDa glucose‐regulated protein (GRP78), induction of ER stress, and the increase in fatty acid synthase and CD36 levels. OPN deficiency in senescent cells also diminished GRP78, the accumulation of intracellular TG, and the increase in CD36 levels. In 20m mice, OPN loss led to increased liver fibrosis. Finally, we showed that OPN expression in vitro and in vivo was regulated by p53. In conclusion, OPN deficiency leads to earlier cellular senescence, ER stress, and TG accumulation during aging. The p53‐OPN axis is required to inhibit the onset of age‐related hepatosteatosis. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
14749718
Volume :
19
Issue :
8
Database :
Complementary Index
Journal :
Aging Cell
Publication Type :
Academic Journal
Accession number :
145205462
Full Text :
https://doi.org/10.1111/acel.13183