Early prenatal undernutrition leads to metabolic dysfunction-associated steatotic liver disease in a rat model of menopause.

Abstract

The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) has increased. MASLD notably increases after menopause in women owing to the drastic reduction in estrogen, which regulates lipid metabolism. While prenatal undernutrition leads to hepatic steatosis after birth, whether prenatal undernutrition affects the onset of postmenopausal MASLD remains unknown. Therefore, we examined the impact of early prenatal undernutrition on the predisposition to postmenopausal MASLD in a rat model of menopause. Pregnant female rats were assigned to the control (CNTL) group, while the undernourished (UN) group was fed 40% of the diet of the control group. Furthermore, both groups were assigned to the ovariectomized (CNTL-OVX/UN-OVX) and sham-operated (CNTL-Sham/UN-Sham) groups at 12 weeks of age. Two-way analysis of variance revealed significant main effects of ovariectomy and prenatal undernutrition on body weight and hepatic triglyceride content. Triglycerides accumulated in the liver at 12 and 24 weeks after ovariectomy, while hepatic steatosis was histologically observed at 24 weeks after ovariectomy in UN-OVX rats. Hepatic gene expression analyses showed an interaction effect between prenatal undernutrition × ovariectomy in ESR1 expression; however, PPARα, RXRα, RARα, Raldh1, and Raldh3 expression was not affected by prenatal undernutrition and ovariectomy. These results suggest that early prenatal undernutrition predisposes postmenopausal women to MASLD by uncovering aberrant estrogen signaling, which may be influenced by estrogen reduction.