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Liver osteopontin is required to prevent the progression of age-related nonalcoholic fatty liver disease.
Aging Cell ( IF 8.0 ) Pub Date : 2020-07-07 , DOI: 10.1111/acel.13183 Beatriz Gómez-Santos 1 , Diego Saenz de Urturi 1 , Maitane Nuñez-García 1 , Francisco Gonzalez-Romero 1 , Xabier Buque 1, 2 , Igor Aurrekoetxea 1, 2 , Virginia Gutiérrez de Juan 3 , Maria J Gonzalez-Rellan 4, 5 , Carmelo García-Monzón 6, 7 , Águeda González-Rodríguez 6, 7 , Lorena Mosteiro 2 , Gaizka Errazti 2 , Patricia Mifsut 2 , Sonia Gaztambide 2 , Luis Castaño 2 , Cesar Martin 8 , Rubén Nogueiras 4, 5 , María L Martinez-Chantar 3, 7 , Wing-Kin Syn 1, 9, 10 , Patricia Aspichueta 1, 2
Aging Cell ( IF 8.0 ) Pub Date : 2020-07-07 , DOI: 10.1111/acel.13183 Beatriz Gómez-Santos 1 , Diego Saenz de Urturi 1 , Maitane Nuñez-García 1 , Francisco Gonzalez-Romero 1 , Xabier Buque 1, 2 , Igor Aurrekoetxea 1, 2 , Virginia Gutiérrez de Juan 3 , Maria J Gonzalez-Rellan 4, 5 , Carmelo García-Monzón 6, 7 , Águeda González-Rodríguez 6, 7 , Lorena Mosteiro 2 , Gaizka Errazti 2 , Patricia Mifsut 2 , Sonia Gaztambide 2 , Luis Castaño 2 , Cesar Martin 8 , Rubén Nogueiras 4, 5 , María L Martinez-Chantar 3, 7 , Wing-Kin Syn 1, 9, 10 , Patricia Aspichueta 1, 2
Affiliation
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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.
中文翻译：
需要肝骨桥蛋白来预防与年龄相关的非酒精性脂肪肝疾病的进展。
骨桥蛋白 (OPN) 是一种衰老相关的分泌表型因子，在非酒精性脂肪肝 (NAFLD) 患者中增加。细胞衰老与年龄依赖性肝脂肪变性有关。因此，我们研究了 OPN 在与年龄相关的肝脂肪变性中的作用。为此，使用了人血清样品、衰老动物模型和诱导衰老的细胞系。测定代谢通量、脂质和蛋白质浓度。在肝脏正常的个体中，我们观察到血清 OPN 水平与年龄增长之间呈正相关。然而，这种与年龄的相关性在 NAFLD 患者中不存在。在野生型 (WT) 小鼠中，血清和肝脏 OPN 在 10 个月大 (m) 以及肝脏 p53 水平增加，并在 20m 时保持升高。与 WT 肝细胞相比，肝脏衰老标志物与 10m OPN 缺陷 (KO) 肝细胞中甘油三酯 (TG) 的合成和浓度有关。10m OPN-KO 小鼠肝脏衰老和脂质代谢的这些变化与 78 kDa 葡萄糖调节蛋白 (GRP78) 的减少、ER 应激的诱导以及脂肪酸合酶和 CD36 水平的增加有关。衰老细胞中的 OPN 缺乏也会减少 GRP78、细胞内 TG 的积累和 CD36 水平的增加。在 20m 小鼠中，OPN 损失导致肝纤维化增加。最后，我们表明体外和体内 OPN 的表达受 p53 调节。总之，OPN 缺乏会导致细胞提前衰老、ER 应激和衰老过程中 TG 的积累。
更新日期：2020-07-07
中文翻译：
需要肝骨桥蛋白来预防与年龄相关的非酒精性脂肪肝疾病的进展。
骨桥蛋白 (OPN) 是一种衰老相关的分泌表型因子，在非酒精性脂肪肝 (NAFLD) 患者中增加。细胞衰老与年龄依赖性肝脂肪变性有关。因此，我们研究了 OPN 在与年龄相关的肝脂肪变性中的作用。为此，使用了人血清样品、衰老动物模型和诱导衰老的细胞系。测定代谢通量、脂质和蛋白质浓度。在肝脏正常的个体中，我们观察到血清 OPN 水平与年龄增长之间呈正相关。然而，这种与年龄的相关性在 NAFLD 患者中不存在。在野生型 (WT) 小鼠中，血清和肝脏 OPN 在 10 个月大 (m) 以及肝脏 p53 水平增加，并在 20m 时保持升高。与 WT 肝细胞相比，肝脏衰老标志物与 10m OPN 缺陷 (KO) 肝细胞中甘油三酯 (TG) 的合成和浓度有关。10m OPN-KO 小鼠肝脏衰老和脂质代谢的这些变化与 78 kDa 葡萄糖调节蛋白 (GRP78) 的减少、ER 应激的诱导以及脂肪酸合酶和 CD36 水平的增加有关。衰老细胞中的 OPN 缺乏也会减少 GRP78、细胞内 TG 的积累和 CD36 水平的增加。在 20m 小鼠中，OPN 损失导致肝纤维化增加。最后，我们表明体外和体内 OPN 的表达受 p53 调节。总之，OPN 缺乏会导致细胞提前衰老、ER 应激和衰老过程中 TG 的积累。
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