Liver osteopontin is required to prevent the progression of age-related nonalcoholic fatty liver disease
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Date
2020-07-07Author
Gómez Santos, Beatriz
Saenz de Urturi Indart, Diego
Nuñez García, Maitane
González Romero, Francisco
Gutiérrez de Juan, Virginia
González Rellán, María Jesús
García Monzón, Carmelo
González Rodríguez, Águeda
Mosteiro González, Lorena
Errazti Olartecoechea, Gaizka
Mifsut Porcel, Patricia
Gaztambide Sáenz, María Sonia
Martín Plágaro, César Augusto
Nogueiras Pozo, Rubén
Syn, Wing-Kin
Aspichueta Celaá, Patricia
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Aging Cell 19(8) : (2020) // e13183
Abstract
[EN] 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 agerelated
hepatosteatosis.
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Except where otherwise noted, this item's license is described as © 2020 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
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