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

Beatriz Gómez‐Santos,Gaizka Errazti,Igor Aurrekoetxea,Lorena Mosteiro,Rubén Nogueiras,Águeda González‐Rodríguez,Patricia Aspichueta,Virginia Gutiérrez De Juan,Patricia Mifsut,Sonia Gaztambide,Diego Sáenz De Urturi ,César San Martín ,Luís Castaño ,Maria J Gonzalez‐Rellan ,Francisco González‐Romero ,Maitane Núñez-García ,Xabier Buqué ,Carmelo García‐Monzón ,Wing‐Kin Syn ,Maria Luz Martínez‐Chantar

doi:10.1111/acel.13183

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.

Highlights

Nonalcoholic fatty liver disease (NAFLD) is one of the most common causes of liver disease in Western countries and includes a spectrum of disorders (Friedman, Neuschwander-Tetri, Rinella, & Sanyal, 2018)
The results showed that the loss of OPN leads to earlier cellular senescence, endoplasmic reticulum (ER) stress, increased de novo lipogenesis, and increased lipid uptake, altogether promoting fatty liver disease
Altered mTOR signaling could be linked to the activation of ER stress (Liu & Sabatini, 2020), the results showed that phosphorylation of mTOR was decreased in OPN-KO mice (Figure S2B), while there was a tendency toward decrease in that of S6 (Figure S2B)

Summary

| INTRODUCTION

Nonalcoholic fatty liver disease (NAFLD) is one of the most common causes of liver disease in Western countries and includes a spectrum of disorders (Friedman, Neuschwander-Tetri, Rinella, & Sanyal, 2018). The results showed that while GRP78, activation of the PERK branch of UPR and p21 levels remained unaltered in HFD-fed 20m OPN-KO mice livers as compared to their HFD-fed 20m WT mice (Figure 6d), levels of γH2AX, indicating DNA damage, were increased as compared to their controls (Figure 6d). The latter was not observed when mice were fed a chow diet (Figure S4B). Over-expression of p53 in vivo, as others performed before (Porteiro, Fondevila, Delgado, et al, 2017), increased liver OPN levels (Figure 7c), even in p53-KO mice (Figure S5A)

| DISCUSSION

Findings

| EXPERIMENTAL PROCEDURES