University of Navarra, Department of Nutrition, Food Science and Physiology, Pamplona, Spain.
University of Navarra, Centre for Nutrition Research, Pamplona, Spain.
Int J Obes (Lond). 2018 Mar;42(3):572-579. doi: 10.1038/ijo.2017.226. Epub 2017 Sep 12.
BACKGROUND/OBJECTIVES: The aim of this study was to characterize the effects of Maresin 1 (MaR1) in obesity-related liver steatosis and the mechanisms involved.
MaR1 effects on fatty liver disease were tested in ob/ob (2-10 μg kg i.p., 20 days) and in diet-induced obese (DIO) mice (2 μg kg, i.p., or 50 μg kg, oral gavage for 10 days), as well as in cultured hepatocytes.
In ob/ob mice, MaR1 reduced liver triglycerides (TG) content, fatty acid synthase (FAS) and stearoyl-CoA desaturase-1 protein expression, while increased acetyl-CoA carboxylase (ACC) phosphorylation and LC3II protein expression, in parallel with a drop in p62 levels. Similar effects on hepatic TG, ACC phosphorylation, p62 and LC3II were observed in DIO mice after MaR1 i.p. injection. Interestingly, oral gavage of MaR1 also decreased serum transaminases, reduced liver weight and TG content. MaR1-treated mice exhibited reduced hepatic lipogenic enzymes content (FAS) or activation (by phosphorylation of ACC), accompanied by upregulation of carnitine palmitoyltransferase (Cpt1a), acyl-coenzyme A oxidase (Acox1) and autophagy-related proteins 5 and 7 (Atg5-7) gene expression, along with increased number of autophagic vacuoles and reduced p62 protein levels. MaR1 also induced AMP-activated protein kinase (AMPK) phosphorylation in DIO mice and in primary hepatocytes, and AMPK inhibition completely blocked MaR1 effects on Cpt1a, Acox1, Atg5 and Atg7 expression.
MaR1 ameliorates liver steatosis by decreasing lipogenic enzymes, while inducing fatty acid oxidation genes and autophagy, which could be related to AMPK activation. Thus, MaR1 may be a new therapeutic candidate for reducing fatty liver in obesity.
背景/目的：本研究旨在探讨maresin 1（MaR1）在肥胖相关肝脂肪变性中的作用及其机制。
采用 ob/ob 肥胖小鼠（腹腔注射 MaR1，2-10μg/kg，20 天）和饮食诱导肥胖（DIO）小鼠（腹腔注射 MaR1，2μg/kg，或灌胃 MaR1，50μg/kg，10 天）以及培养的肝细胞模型，检测 MaR1 对脂肪肝的作用。
在 ob/ob 肥胖小鼠中，MaR1 降低了肝组织三酰甘油（TG）含量、脂肪酸合酶（FAS）和硬脂酰辅酶 A 去饱和酶 1（SCD-1）蛋白表达，同时增加了乙酰辅酶 A 羧化酶（ACC）磷酸化和微管相关蛋白 1 轻链 3 转化体 II（LC3II）蛋白表达，同时降低了 p62 水平。在 DIO 肥胖小鼠中，腹腔注射 MaR1 后，肝组织 TG、ACC 磷酸化、p62 和 LC3II 也出现了类似的变化。有趣的是，MaR1 灌胃也降低了血清转氨酶，减轻了肝脏重量和 TG 含量。MaR1 处理的小鼠肝组织中脂肪生成酶（FAS）含量或激活（通过 ACC 磷酸化）降低，同时肉碱棕榈酰转移酶（CPT1a）、酰基辅酶 A 氧化酶（Acox1）和自噬相关蛋白 5 和 7（Atg5-7）基因表达上调，自噬小体数量增加，p62 蛋白水平降低。MaR1 还诱导了 DIO 肥胖小鼠和原代肝细胞中 AMP 激活的蛋白激酶（AMPK）磷酸化，而 AMPK 抑制完全阻断了 MaR1 对 CPT1a、Acox1、Atg5 和 Atg7 表达的影响。
MaR1 通过降低脂肪生成酶，同时诱导脂肪酸氧化基因和自噬，从而改善肝脂肪变性，这可能与 AMPK 激活有关。因此，MaR1 可能是治疗肥胖相关脂肪肝的一种新的治疗候选药物。
