Undernourishment in utero and hepatic steatosis in later life: A potential issue in Japanese people

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.