Itoh Hiroaki, Muramatsu-Kato Keiko, Ferdous Urmi J, Kohmura-Kobayashi Yukiko, Kanayama Naohiro
Department of Obstetrics and Gynecology, Hamamatsu University School of Medicine, Hamamatsu, Japan.
Congenit Anom (Kyoto). 2017 Nov;57(6):178-183. doi: 10.1111/cga.12200. Epub 2017 Mar 22.
Nonalcoholic fatty liver disease (NAFLD) is a hepatic manifestation of metabolic syndrome. The prevalence of NAFLD in Japan has nearly doubled in the last 10-15 years. Increasing evidence supports undernourishment in utero being causatively connected with the risk of NAFLD in later life. Low body mass index (BMI) has been common among Japanese women of childbearing age for several decades due to their strong desire to be thin. It is plausible that insufficient maternal energy intake by pregnant Japanese women may underlie the rapid increase in the prevalence of NAFLD in Japan. In order to clarify the mechanisms by which undernourishment in utero primes adult hepatic steatosis, we developed a mouse model of fetal undernourishment with a hepatic fat deposit-prone phenotype on an obesogenic high fat diet in later life. We found that endoplasmic reticulum (ER) stress response parameters were activated concomitantly with the deterioration of hepatic steatosis and also that the alleviation of ER stress with the chemical chaperone, tauroursodeoxycholic acid (TUDCA), significantly improved hepatic steatosis. Therefore, undernourishment in utero may program the future integration of ER stress in the liver on an obesogenic diet in later life and also induce the deterioration of hepatic steatosis. These results also provide an insight into interventions for the potential high-risk population of NAFLD, such as those born small or exposed to maternal undernourishment during the fetal period, with the alleviation of ER stress by dietary supplements and/or specific food including chaperones.
非酒精性脂肪性肝病（NAFLD）是代谢综合征的一种肝脏表现。在过去10至15年中，日本NAFLD的患病率几乎翻了一番。越来越多的证据支持子宫内营养不良与晚年患NAFLD的风险存在因果关系。几十年来，由于强烈的瘦身愿望，低体重指数（BMI）在日本育龄女性中很常见。日本孕妇孕期能量摄入不足可能是日本NAFLD患病率迅速上升的原因。为了阐明子宫内营养不良引发成年期肝脏脂肪变性的机制，我们建立了一种胎儿营养不良的小鼠模型，该模型在晚年易致肥胖的高脂饮食下具有肝脏脂肪沉积倾向的表型。我们发现，内质网（ER）应激反应参数随着肝脏脂肪变性的恶化而被激活，并且用化学伴侣牛磺熊去氧胆酸（TUDCA）减轻ER应激可显著改善肝脏脂肪变性。因此，子宫内营养不良可能会在晚年使肝脏在致肥胖饮食时对ER应激产生未来整合作用，并导致肝脏脂肪变性恶化。这些结果也为NAFLD潜在高危人群的干预措施提供了思路，比如那些出生时体重小或在胎儿期暴露于母体营养不良的人群，可通过膳食补充剂和/或包括伴侣分子在内的特定食物减轻ER应激。
