University College London, Institute of Liver and Digestive Health, Center for Fatty Liver and Repair-Regeneration Research, Royal Free Hospital, London, UK.
Hepatology. 2013 Jul;58(1):128-38. doi: 10.1002/hep.26248. Epub 2013 May 31.
The global prevalence of obesity-induced liver disease (nonalcoholic fatty liver disease; NAFLD) is rising. Suggested causes include a role for in utero influences of maternal obesity compounded by the availability of energy-dense foods throughout postnatal life. Using a physiologically relevant model, we investigated the role of the innate immune system in liver injury induced by maternal obesity followed by a postnatal obesogenic diet. Female C57BL/6J mice were fed a standard or obesogenic diet before and throughout pregnancy and during lactation. Female offspring were weaned onto a standard or obesogenic diet at 3 weeks postpartum. Biochemical and histological indicators of dysmetabolism, NAFLD and fibrosis, analysis of profibrotic pathways, liver innate immune cells, and reactive oxygen species (ROS) were investigated at 3, 6, and 12 months. Female offspring exposed to a postweaning obesogenic diet (OffCon-OD) demonstrated evidence of liver injury, which was exacerbated by previous exposure to maternal obesity (OffOb-OD), as demonstrated by raised alanine aminotransferase, hepatic triglycerides, and hepatic expression of interleukin (IL)-6, tumor necrosis factor alpha, transforming growth factor beta, alpha smooth muscle actin, and collagen (P < 0.01). Histological evidence of hepatosteatosis and a more-robust NAFLD phenotype with hepatic fibrosis was observed at 12 months in OffOb-OD. A role for the innate immune system was indicated by increased Kupffer cell numbers with impaired phagocytic function and raised ROS synthesis (P < 0.01), together with reduced natural killer T cells and raised interleukin (IL)-12 and IL-18.
Maternal obesity in the context of a postnatal hypercalorific obesogenic diet aggressively programs offspring NAFLD associated with innate immune dysfunction, resulting in a comprehensive phenotype that accurately reflects the human disease.
肥胖引起的肝脏疾病（非酒精性脂肪性肝病；NAFLD）的全球患病率正在上升。其发病原因可能包括：母体肥胖对胎儿的宫内影响，再加上出生后一生中高热量食物的供应。我们采用一种生理相关的模型，研究了母体肥胖继之后的产后致肥胖饮食引起的肝损伤中固有免疫系统的作用。雌性 C57BL/6J 小鼠在怀孕前、怀孕期间和哺乳期前均喂食标准饮食或致肥胖饮食，产后 3 周开始，雌性后代喂食标准饮食或致肥胖饮食。在 3、6 和 12 个月时，检测了代谢紊乱、NAFLD 和纤维化的生化和组织学指标、纤维化途径分析、肝固有免疫细胞和活性氧（ROS）。在接触产后致肥胖饮食（OffCon-OD）的雌性后代中，观察到了肝损伤的证据，之前暴露于母体肥胖（OffOb-OD）加剧了这种损伤，表现为丙氨酸氨基转移酶升高、肝甘油三酯升高和白细胞介素（IL）-6、肿瘤坏死因子-α、转化生长因子-β、α平滑肌肌动蛋白和胶原的肝表达增加（P<0.01）。在 12 个月时，在 OffOb-OD 中观察到了肝脂肪变性和更明显的 NAFLD 表型伴肝纤维化的组织学证据。固有免疫系统的作用表明，Kupffer 细胞数量增加，吞噬功能受损，ROS 合成增加（P<0.01），同时自然杀伤 T 细胞减少，白细胞介素（IL）-12 和 IL-18 增加。
产后高热量致肥胖饮食背景下的母体肥胖会强烈影响后代的 NAFLD，与固有免疫功能障碍有关，导致准确反映人类疾病的综合表型。
