Yang Fan, Dai Yanyan, Min Cuiting, Li Xiaonan
1Department of Child Health Care, Children's Hospital of Nanjing Medical University, 72 Guangzhou Road, Nanjing, China.
2Institute of Paediatric Research, Nanjing Medical University, 140 Hanzhong Road, Nanjing, China.
Nutr Metab (Lond). 2018 May 2;15:30. doi: 10.1186/s12986-018-0272-0. eCollection 2018.
Postnatal overfeeding activates tissue glucocorticoid (GC) activity by up-regulating 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) and increasing sensitivity to high-fat (HF) diet-induced non-alcoholic fatty liver disease (NAFLD). The present study aimed to evaluate the effects of postnatal overfeeding on GC regulation and lipogenesis in the liver and to observe the impact of GC on hepatocyte lipid metabolism.
In vivo Male Sprague-Dawley rat pup litters were adjusted to litter sizes of three (small litter, SL) or ten (normal litter, NL) on postnatal day 3 and then given standard chow from postnatal week 3 (W3) to W13. In vitro HepG2 cells were stimulated by GC, mifepristone (Mi) or GC + Mi within 48 h, followed by sodium oleate (OA) intervention (or not) for 24 h. Intracellular lipid droplets, triglyceride (TG) concentrations and gene expression related to lipid metabolism were measured in hepatic tissues or HepG2 cells.
In vivo weight gain in the body and liver and TG concentrations in the liver were significantly increased in the SL rats compared to the NL rats at W3 and W13 ( < 0.05); mRNA expression of hepatic 11β-HSD1, acetyl-CoA carboxylase 1 (ACC), stearoyl-CoA desaturase-1 (SCD1), fatty acid synthase (FASN) and their nuclear transcription factor, sterol regulatory element binding protein-1c (SREBP-1c) ( < 0.05), was also increased. In vitro, intracellular lipid droplets and TG content in HepG2 cells increased under stimulation with GC or OA ( < 0.05); the increase was more significant following treatment with GC and OA together ( < 0.05). The ACC, SCD1, FASN and SREBP-1c mRNA expression changes were highly similar to the changes in TG content in cells. All the changes induced by GC disappeared when the glucocorticoid receptor (GR) was blocked by Mi.
Postnatal overfeeding induced GC overexposure through 11β-HSD1 up-regulation in the liver. GC activated hepatic de novo lipogenesis (DNL) via GR and led to hepatic lipid accumulation, which increased the risk of NAFLD during adulthood.
产后过度喂养通过上调11β-羟基类固醇脱氢酶1（11β-HSD1）并增加对高脂（HF）饮食诱导的非酒精性脂肪性肝病（NAFLD）的敏感性来激活组织糖皮质激素（GC）活性。本研究旨在评估产后过度喂养对肝脏中GC调节和脂肪生成的影响，并观察GC对肝细胞脂质代谢的影响。
体内实验：在出生后第3天，将雄性Sprague-Dawley大鼠幼崽的窝仔数调整为3只（小窝仔，SL）或10只（正常窝仔，NL），然后从出生后第3周（W3）至第13周给予标准饲料。体外实验：在48小时内用GC、米非司酮（Mi）或GC + Mi刺激HepG2细胞，随后（或不）用油酸（OA）干预24小时。测量肝组织或HepG2细胞中的细胞内脂滴、甘油三酯（TG）浓度以及与脂质代谢相关的基因表达。
体内实验：与NL大鼠相比，SL大鼠在W3和W13时体重、肝脏重量增加以及肝脏TG浓度显著升高（<0.05）；肝脏11β-HSD1、乙酰辅酶A羧化酶1（ACC）、硬脂酰辅酶A去饱和酶-1（SCD1）、脂肪酸合酶（FASN）及其核转录因子固醇调节元件结合蛋白-1c（SREBP-1c）的mRNA表达也增加（<0.05）。体外实验：在GC或OA刺激下，HepG2细胞内的脂滴和TG含量增加（<0.05）；GC和OA共同处理后增加更显著（<0.05）。ACC、SCD1、FASN和SREBP-1c的mRNA表达变化与细胞内TG含量变化高度相似。当Mi阻断糖皮质激素受体（GR）时，GC诱导的所有变化均消失。
产后过度喂养通过上调肝脏中的11β-HSD1诱导GC过度暴露。GC通过GR激活肝脏从头脂肪生成（DNL）并导致肝脏脂质积累，这增加了成年期患NAFLD的风险。
